Compounds

ABSTRACT

The present invention relates to substituted triazole compounds of the formula (I): 
     
       
         
         
             
             
         
       
     
     and salts thereof, to pharmaceutical compositions containing them and their use in medicine. In particular, the invention relates to compounds for inhibiting SCD activity.

COMPOUNDS

This application is a divisional of application Ser. No. 12/741,629,filed 9 Aug. 2010, which is a §371 national stage entry of InternationalApplication No. PCT/EP2008/065105, filed 7 Nov. 2008, which claims thebenefit of priority of GB Application No. 0722075.9, filed 9 Nov. 2007,which are incorporated herein in their entireties.

FIELD OF THE INVENTION

The present invention relates to a novel class of compounds believed tobe inhibitors of stearoyl-CoA desaturase (SCD), compositions comprisingsaid compounds, methods of synthesis and uses for such compounds intreating and/or preventing various diseases, including those mediated bySCD enzyme, such as diseases related to elevated lipid levels,cardiovascular disease, diabetes, obesity, metabolic syndrome, skindisorders such as acne, diseases or conditions related to cancer and thetreatment of symptoms linked to the production of the amyloidplaque-forming Aβ42 peptide such as Alzheimer's disease and the like.

BACKGROUND OF THE INVENTION

Acyl desaturase enzymes catalyze the formation of double bonds in fattyacids derived from either dietary sources or de novo synthesis in theliver. Mammals synthesise at least three fatty acid desaturases ofdiffering chain length that specifically catalyze the addition of doublebonds at the delta-9, delta-6, and delta-5 positions. Stearoyl-CoAdesaturases (SCDs) introduce a double bond in the C9-C10 position ofsaturated fatty acids. The preferred substrates for the enzymes arepalmitoyl-CoA (16:0) and stearoyl-CoA (18:0), which are converted topalmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), respectively. Theresulting mono-unsaturated fatty acids may then be employed in thepreparation of phospholipids, triglycerides, and cholesteryl esters, invivo.

A number of mammalian SCD genes have been cloned. For example, two geneshave been cloned from rats (SCD1, SCD2) and four SCD genes have beenisolated from mice (SCD1, 2, 3 and 4). While the basic biochemical rolesof SCD has been known in rats and mice since the 1970′s (Jeffcoat, R etal., Elsevier Science (1984), Vol 4, pp. 85-112; de Antueno, R J, Lipids(1993), Vol. 28, No. 4, pp. 285-290), it has only recently been directlyimplicated in human diseases processes.

A single SCD gene, SCD1, has been characterized in humans. SCD1 isdescribed in Brownlie et al, WO 01/62954. A second human SCD isoform hasbeen identified, and because it bears little sequence homology to knownmouse or rat isoforms it has been named human SCD5 or hSCD5 (WO02/26944).

Whilst not wishing to be bound by theory, it is thought that inhibitionof the activity of SCD in vivo can be used to ameliorate and/or treatone or more diseases such as dyslipidemia, hypoalphalipoproteinemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial hypercholesterolemia, angina, ischemia, cardiac ischemia,stroke, myocardial infarction, atherosclerosis, obesity, Type Idiabetes, Type II diabetes, insulin resistance, hyperinsulinaemia,metabolic syndrome; other cardiovascular diseases e.g. peripheralvascular disease, reperfusion injury, angioplastic restenosis,hypertension, vascular complications of diabetes, thrombosis; hepaticsteatosis, non-alcoholic steatohepatitis (NASH) and other diseasesrelated to accumulation of lipids in the liver.

An SCD-mediated disease or condition also includes a disorder ofpolyunsaturated fatty acid (PUFA) disorder, or a skin disorder,including but not limited to eczema, acne, psoriasis, skin ageing,keloid scar formation or prevention, diseases related to production orsecretions from mucous membranes, such as monounsaturated fatty acids,wax esters, and the like (U.S.2006/0205713A1, WO2007/046868,WO2007/046867). SCD has been shown to play a physiological role incholesterol homeostasis and the de novo biosynthesis of cholesterolesters, triglycerides and wax esters required for normal skin and eyelidfunction and therefore may be useful in the treatment of acne and otherskin conditions (Makoto et al. J of Nutrition (2001), 131(9),2260-2268,Harrison et al. J of Investigative Dermatology (2007) 127(6),1309-1317).

An SCD-mediated disease or condition also includes but is not limited toa disease or condition which is, or is related to cancer, neoplasia,malignancy, metastases, tumours (benign or malignant), carcinogenesis,hepatomas and the like (U.S.2006/0205713A1, WO2007/046868,WO2007/046867). Recently, SCD-1 has been identified as playing a role inhuman tumor cell survival and therefore has potential as an anticancertarget (Morgan-Lappe et al. 2007 Cancer Res. 67(9) 4390-4398).

It has been shown that overexpression of Steroyl-CoA desaturase (SCD) inhuman cells in culture leads to a specific increase in the production ofthe amyloid plaque-forming Aβ42 peptide, and conversely, that reductionsin SCD activity in human cells in culture leads to a specific decreasein the production of Aβ42. Therefore, SCD inhibitors may also be usefulfor treating, delaying the onset of symptoms, or slowing the progressionof symptoms of mild cognitive impairment (MCI), Alzheimer's Disease(AD), cerebral amyloid angiopathy (CAA) or dementia associated with DownSyndrome (DS) and other neurodegenerative diseases characterized by theformation or accumulation of amyloid plaques comprising Aβ42(U.S.2007/0087363A1; Myriad Genetics).

WO2005/011657 describes certain piperazine derivatives useful forinhibiting SCD activity.

The present invention provides a compound of formula (I) for inhibitingSCD activity:

wherein:

X represents —CONH—, —NHCO— or —CH₂NH—;

R¹ represents:

—C₆₋₁₀aryl (such as phenyl) optionally substituted by one, two or threegroups independently selected from:

-   -   —C₁₋₃alkyl (such as —CH₃), —C₁₋₆alkoxy (such as —OCH₃),        —C₁₋₆haloalkyl (such as —CF₃), —OC₁₋₆haloalkyl (such as —OCF₃),        —OC₃₋₆cycloalkyl or halogen (such as chloro, bromo or fluoro);

R² represents hydrogen, —C₁₋₆alkyl (such as —CH₃) or—C₁₋₃alkylOC₁₋₃alkyl (such as —CH₂OCH₃);

R³ represents:

—C₅₋₉heteroaryl optionally substituted by one, two or three groupsindependently selected from: —C₁₋₃alkyl (such as —CH₃), —C₁₋₆alkoxy(such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylNR⁷R⁸,—C(═O)NHC₁₋₃alkylOC₁₋₃alkyl, —C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH(such as —CH₂OH or —C₂H₄OH), —C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl (such as —CF₃), —OC₁₋₆haloalkyl(such as —OCF₃), —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl, or halogen (such aschloro, bromo or fluoro);

R⁴ represents —H or —C₁₋₃alkyl (such as —CH₃ or —C₂H₅);

R⁵ represents —H or —C₁₋₃alkyl (such as —CH₃);

R⁶ represents —H or —C₁₋₆alkyl (such as —CH₃);

R⁷ represents —H or —C₁₋₃alkyl (such as —CH₃);

R⁸ represents —H or —C₁₋₃alkyl (such as —CH₃); and

R⁹ represents —C₆heterocycle (such as morpholine or piperazine) which isoptionally substituted by a group independently selected from:—C₁₋₆alkyl (such as —CH₃);

or a pharmaceutically acceptable salt thereof,

with the proviso that the compound of formula (I) is not

N-1,3-benzodioxol-5-yl-1-[(4-flurophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide

orN-(6-acetyl-1,3-benzodioxol-5-yl)-1-[(4-methylphenyl)methyl]-1H-1,2,3-triazole-4-carboxamide

The said compounds have been found to inhibit SCD activity and maytherefore be useful in the treatment of SCD-mediated diseases such asdiseases or conditions caused by or associated with an abnormal plasmalipid profile including dyslipidemia, hypoalphalipoproteinemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial hypercholesterolemia, angina, ischemia, cardiac ischemia,stroke, myocardial infarction, atherosclerosis, obesity, Type Idiabetes, Type II diabetes, insulin resistance, hyperinsulinaemia andmetabolic syndrome; other cardiovascular diseases e.g. peripheralvascular disease, reperfusion injury, angioplastic restenosis,hypertension, vascular complications of diabetes, thrombosis, hepaticsteatosis, non-alcoholic steatoheptatis (NASH) and other diseasesrelated to accumulation of lipids in the liver; skin disorders e.g.eczema, acne, psoriasis, skin ageing, keloid scar formation orprevention, and diseases related to production or secretions from mucousmembranes; cancer, neoplasia, malignancy, metastases, tumours (benign ormalignant), carcinogenesis, hepatomas and the like; mild cognitiveimpairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy(CAA) or dementia associated with Down Syndrome (DS) and otherneurodegenerative diseases characterized by the formation oraccumulation of amyloid plaques comprising Aβ42.

In one aspect of the invention, X represents —CONH—. In another aspectof the invention, X represents —NHCO—. In another aspect of theinvention, X represents —CH₂NH—.

In one aspect of the invention, R¹ represents phenyl optionallysubstituted by one, two or three groups independently selected from:—C₁₋₃alkyl (such as —CH₃), —C₁₋₆alkoxy (such as —OCH₃), —C₁₋₆haloalkyl(such as —CF₃), —OC₁₋₆haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl orhalogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionallysubstituted by one or two groups independently selected from: —C₁₋₃alkyl(such as —CH₃), —C₁₋₆alkoxy (such as —OCH₃), —C₁₋₆haloalkyl (such as—CF₃), —OC₁₋₆haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl or halogen(such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionallysubstituted by one, two or three groups independently selected from:—C₁₋₃alkyl (such as —CH₃), —C₁₋₃alkoxy (such as —OCH₃), —C₁₋₃haloalkyl(such as —CF₃), —OC₁₋₃haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl orhalogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionallysubstituted by one or two groups independently selected from: —C₁₋₃alkyl(such as —CH₃), —C₁₋₃alkoxy (such as —OCH₃), —C₁₋₃haloalkyl (such as—CF₃), —OC₁₋₃haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl or halogen(such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionallysubstituted by one, two or three groups independently selected from:—CH₃, —OCH₃, —CF₃, —OCF₃ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl optionallysubstituted by one or two groups independently selected from: —CH₃,—OCH₃, —CF₃, —OCF₃ or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R¹ represents phenyl substituted bytwo groups independently selected from halogen (such as chloro, bromo orfluoro).

In another aspect of the invention, R¹ represents phenyl substituted bytwo chloro groups.

In another aspect of the invention, R¹ is phenyl substituted in the metaposition, that is in the 3 position, and the para position, that is inthe 4 position, by halogen e.g chloro i.e.

In another aspect of the invention, R¹ is phenyl substituted in the metaposition, that is in the 3 position and 5 position, by halogen e.gchloro i.e

In another aspect of the invention, R¹ represents phenyl.

In one aspect of the invention, R² represents hydrogen. In anotheraspect of the invention, R² represents —C₁₋₆alkyl. In another aspect ofthe invention, R² represents —C₁₋₃alkyl. In another aspect of theinvention, R² represents —CH₃ (methyl). In another aspect of theinvention, R² represents —C₁₋₃alkylOC₁₋₃alkyl. In another aspect of theinvention, R² represents —CH₂OCH₃. In another aspect of the invention,R² represents hydrogen or —C₁₋₃alkyl.

In one aspect of the invention, R³ represents a —C₅₋₉heteroaryl whereinthe optional substituent is on a carbon atom.

In another aspect of the invention, R³ represents —C₅heteroarylcontaining 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen, oxygen or sulphur and theremaining ring-atoms are carbon, optionally substituted by one, two orthree groups independently selected from: —C₁₋₃alkyl (such as —CH₃),—C₁₋₆alkoxy (such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH (such as —CH₂OH or —C₂H₄OH),—C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₃alkyl, —C₁₋₆haloalkyl(such as —CF₃), —OC₁₋₆haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl,—C₃₋₆cycloalkyl or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R³ represents —O₅heteroarylcontaining 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen, oxygen or sulphur and theremaining ring-atoms are carbon, optionally substituted by one or twogroups independently selected from: —C₁₋₃alkyl (such as —CH₃),—C₁₋₆alkoxy (such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH (such as —CH₂OH or —C₂H₄OH),—C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyI(such as —CF₃), ^(—OC) ₁₋₆haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl,—C₃₋₆cycloalkyl or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R³ represents —C₅heteroarylcontaining 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen, oxygen or sulphur and theremaining ring-atoms are carbon, optionally substituted by one, two orthree groups independently selected from: —C₁₋₃alkyl (such as —CH₃),—C₁₋₃alkoxy (such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₃alkylOH (such as —CH₂OH or —C₂H₄OH),—C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl or—C₁₋₃haloalkyl (such as —CF₃).

In another aspect of the invention, R³ represents —C₅heteroarylcontaining 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen, oxygen or sulphur and theremaining ring-atoms are carbon, optionally substituted by one or twogroups independently selected from: —C₁₋₃alkyl (such as —CH₃),—C₁₋₃alkoxy (such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₃alkylOH (such as —CH₂OH or —C₂H₄OH),—C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl or—C₁₋₃haloalkyl (such as —CF₃).

In another aspect of the invention, R³ represents —C₅heteroarylcontaining 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen, oxygen or sulphur and theremaining ring-atoms are carbon, optionally substituted by one, two orthree groups independently selected from: —C₁₋₃alkyl (such as —CH₃),—CO₂R⁴, —C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylN(CH₃)₂,—C(═O)NHC₁₋₃alkylOC₁₋₃alkyl, —C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₃alkylOH(such as —CH₂OH or —C₂H₄OH), —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl or —C₁₋₃haloalkyl (such as —CF₃).

In another aspect of the invention, R³ represents —C₅heteroarylcontaining 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen, oxygen or sulphur and theremaining ring-atoms are carbon, optionally substituted by one or twogroups independently selected from: —C₁₋₃alkyl (such as —CH₃), —CO₂R⁴,—C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylN(CH₃)₂, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₃alkylOH (such as —CH₂OH or —C₂H₄OH),—CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl or —C₁₋₃haloalkyl(such as —CF₃).

In another aspect of the invention, R³ represents —C₅heteroarylcontaining 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen, oxygen or sulphur and theremaining ring-atoms are carbon, optionally substituted by one, two orthree groups independently selected from: —CH₃, —CO₂H, —CO₂CH₃,—CO₂C₂H₅, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)NHC₂H₅, —C(═O)NHCH(CH₃)₂,—C(═O)NHC₂H₄CH(CH₃)₂, —C(═O)N(CH₃)₂ —C(═O)NHC₂H₄N(CH₃)₂, —C(═O)NHC₂H₄OH,—C(═O)NHC₂H₄OCH₃, —C(═O)R⁹, —CH₂OH, —C₂H₄OH, —CHO, —CH₂CO₂CH₃,—CH₂CO₂C₂H₅ —CH₂OCH₃, —CH₂CONHCH₃ or —CF₃.

In another aspect of the invention, R³ represents —C₅heteroarylcontaining 5 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen, oxygen or sulphur and theremaining ring-atoms are carbon, optionally substituted by one or twogroups independently selected from: —CH₃, —CO₂H, —CO₂CH₃, —CO₂C₂H₅,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)NHC₂H₅, —C(═O)NHCH(CH₃)₂,—C(═O)NHC₂H₄CH(CH₃)₂, —C(═O)N(CH₃)₂ —C(═O)NHC₂H₄N(CH₃)₂, —C(═O)NHC₂H₄OH,—C(═O)NHC₂H₄OCH₃, —C(═O)R⁹, —CH₂OH, —C₂H₄OH, —CHO, —CH₂CO₂CH₃,—CH₂CO₂C₂H₅ —CH₂OCH₃ , —CH₂CONHCH₃ or —CF₃.

In another aspect of the invention, R³ represents thiazole, thiadiazole,oxadiazole or oxazole, optionally substituted by one, two or threegroups independently selected from: —CH₃, —CO₂H, —CO₂CH₃, —CO₂C₂H₅,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)NHC₂H₅, —C(═O)NHCH(CH₃)₂,—C(═O)NHC₂H₄CH(CH₃)₂, —C(═O)N(CH₃)₂ —C(═O)NHC₂H₄N(CH₃)₂, —C(═O)NHC₂H₄OH,—C(═O)NHC₂H₄OCH₃, —C(═O)R⁹, —CH₂OH, —C₂H₄OH, —CHO, —CH₂CO₂CH₃,—CH₂CO₂C₂H₅ —CH₂OCH₃ , —CH₂CONHCH₃ or —CF₃.

In another aspect of the invention, R³ represents thiazole, thiadiazole,oxadiazole or oxazole, optionally substituted by one or two groupsindependently selected from: —CH₃, —CO₂H, —CO₂CH₃, —CO₂C₂H₅, —C(═O)N H₂,—C(═O)NHCH₃, —C(═O)NHC₂H₅, —C(═O)NHCH(CH₃)₂, —C(═O)NHC₂H₄CH(CH₃)₂,—C(═O)N(CH₃)₂ —C(═O)NHC₂H₄N(CH₃)₂, —C(═O)NHC₂H₄OH, —C(═O)NHC₂H₄OCH₃,—C(═O)R⁹, —CH₂OH, —C₂H₄OH, —CHO, —CH₂CO₂CH₃, —CH₂CO₂C₂H₅ —CH₂OCH₃ ,—CH₂CONHCH₃ or —CF₃.

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one, two or threegroups independently selected from: —C₁₋₃alkyl (such as —CH₃),—C₁₋₆alkoxy (such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH (such as —CH₂OH or —C₂H₄OH),—C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl(such as —CF₃), —OC₁₋₆haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl,—C₃₋₆cycloalkyl or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one or two groupsindependently selected from: —C₁₋₃alkyl (such as —CH₃), —C₁₋₆alkoxy(such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylNR⁷R⁸,—C(═O)NHC₁₋₃alkylOC₁₋₃alkyl, —C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH(such as —CH₂OH or —C₂H₄OH), —C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl (such as —CF₃), ^(—OC) ₁₋₆haloalkyl(such as —OCF₃), —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl or halogen (such aschloro, bromo or fluoro).

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one, two or threegroups independently selected from: —C₁₋₃alkyl (such as —CH₃),—C₁₋₃alkoxy (such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₃alkylOH (such as —CH₂OH or —C₂H₄OH),—C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₃alkyl, —C₁₋₃haloalkyl(such as —CF₃), —OC₁₋₃haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl,—C₃₋₆cycloalkyl or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one or two groupsindependently selected from: —C₁₋₃alkyl (such as —CH₃), —C₁₋₃alkoxy(such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylNR⁷R⁸,—C(═O)NHC₁₋₃alkylOC₁₋₃alkyl, —C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₃alkylOH(such as —CH₂OH or —C₂H₄OH), —C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₃haloalkyl (such as —CF₃), —OC₁₋₃haloalkyl(such as —OCF₃), —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl or halogen (such aschloro, bromo or fluoro).

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one, two or threegroups independently selected from: —C₁₋₆alkoxy (such as —OCH₃), —CO₂R⁴or —C═O.

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one or two groupsindependently selected from: —C₁₋₆alkoxy (such as —OCH₃), —CO₂R⁴ or—C═O.

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one, two or threegroups independently selected from: —C₁₋₃alkoxy (such as —OCH₃), —CO₂R⁴or —C═O.

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one or two groupsindependently selected from: —C₁₋₃alkoxy (such as —OCH₃), —CO₂R⁴ or—C═O.

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one, two or threegroups independently selected from: —OCH₃, —CO₂C₁₋₃alkyl or —C═O.

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one or two groupsindependently selected from: —OCH₃, —CO₂C₁₋₃alkyl or —C═O.

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one, two or threegroups independently selected from: —OCH₃, —CO₂C₂H₅ or —C═O.

In another aspect of the invention, R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one or two groupsindependently selected from: —OCH₃, —CO₂C₂H₅ or —C═O.

In another aspect of the invention, R³ represents benzothiazole orthiazolo-pyrimidin, optionally substituted by one, two or three groupsindependently selected from: —OCH₃, —CO₂C₂H₅ or —C═O.

In another aspect of the invention, R³ represents benzothiazole orthiazolo-pyrimidin, optionally substituted by one or two groupsindependently selected from: —OCH₃, —CO₂C₂H₅ or —C═O.

In another aspect of the invention, R³ represents —C₆heteroaryloptionally substituted by one, two or three groups independentlyselected from: —C₁₋₃alkyl (such as —CH₃), —C₁₋₆alkoxy (such as —OCH₃),—CO₂R⁴, —C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylNR⁷R⁸,—C(═O)NHC₁₋₃alkylOC₁₋₃alkyl, —C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH(such as —CH₂OH or —C₂H₄OH), —C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl (such as —CF₃), —OC₁₋₆haloalkyl(such as —OCF₃), —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl or halogen (such aschloro, bromo or fluoro).

In another aspect of the invention, R³ represents —C₆heteroaryloptionally substituted by one or two groups independently selected from:—C₁₋₃alkyl (such as —CH₃), —C₁₋₆alkoxy (such as —OCH₃), —CO₂R⁴,—C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH (such as —CH₂OH or —C₂H₄OH),—C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl(such as —CF₃), —OC₁₋₆haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl,—C₃₋₆cycloalkyl or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R³ represents —C₆heteroaryloptionally substituted by one, two or three groups independentlyselected from: —C₁₋₃alkyl (such as —CH₃), —C₁₋₃alkoxy (such as —OCH₃),—CO₂R⁴, —C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylNR⁷R⁸,—C(═O)NHC₁₋₃alkylOC₁₋₃alkyl, —C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₃alkylOH(such as —CH₂OH or —C₂H₄OH), —C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₃haloalkyl (such as —CF₃), —OC₁₋₃haloalkyl(such as —OCF₃), —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl or halogen (such aschloro, bromo or fluoro).

In another aspect of the invention, R³ represents pyridine optionallysubstituted by one or two groups independently selected from: —C₁₋₃alkyl(such as —CH₃), —C₁₋₃alkoxy (such as —OCH₃), —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₃alkylOH (such as —CH₂OH or —C₂H₄OH),—C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₃alkyl, —C₁₋₃haloalkyl(such as —CF₃), —OC₁₋₃haloalkyl (such as —OCF₃), —OC₃₋₆cycloalkyl,—C₃₋₆cycloalkyl or halogen (such as chloro, bromo or fluoro).

In another aspect of the invention, R³ represents pyridine optionallysubstituted by one, two or three groups independently selected from:—CO₂R⁴, —C₁₋₆alkylOH (such as —CH₂OH or —C₂H₄OH) or —C(═O)NR⁵R⁶.

In another aspect of the invention, R³ represents pyridine optionallysubstituted by one or two groups independently selected from: —CO₂R⁴,—C₁₋₆alkylOH (such as —CH₂OH or —C₂H₄OH) or —C(═O)NR⁵R⁶.

In another aspect of the invention, R³ represents pyridine optionallysubstituted by one, two or three groups independently selected from:—CO₂R⁴, —C₁₋₃alkylOH (such as —CH₂OH or —C₂H₄OH) or —C(═O)NR⁵R⁶.

In another aspect of the invention, R³ represents pyridine optionallysubstituted by one or two groups independently selected from: —CO₂R⁴,—C₁₋₃alkylOH (such as —CH₂OH or —C₂H₄OH) or —C(═O)NR⁵R⁶.

In another aspect of the invention, R³ represents pyridine optionallysubstituted by a group independently selected from: —CO₂R⁴, —C₁₋₃alkylOH(such as —CH₂OH or —C₂H₄OH) or —C(═O)NR⁵R⁶.

In another aspect of the invention, R³ represents pyridine optionallysubstituted by a group independently selected from: —CO₂CH₃, —CH₂OH or—CON HCH₃.

In one aspect of the invention, R⁴ represents hydrogen. In anotheraspect of the invention, R⁴ represents —C₁₋₃alkyl. In another aspect ofthe invention, R⁴ represents —C₂H₅ (ethyl). In another aspect of theinvention, R⁴ represents —CH₃ (methyl).

In one aspect of the invention, R⁵ represents hydrogen. In anotheraspect of the invention R⁵ represents —C₁₋₃alkyl. In another aspect ofthe invention R⁵ represents —CH₃ (methyl).

In one aspect of the invention, R⁶ represents hydrogen. In anotheraspect of the invention,

R⁶ represents —C₁₋₆alkyl. In another aspect of the invention R⁶represents —C₁₋₃alkyl. In another aspect of the invention, R⁶ represents—CH₃ (methyl). In another aspect of the invention, R⁶ represents—CH(CH₃)₂ (isopropyl). In another aspect of the invention, R⁶ represents—C₂H₅ (ethyl). In another aspect of the invention, R⁶ represents —C₃H₇(propyl).

In one aspect of the invention, R⁷ represents hydrogen. In anotheraspect of the invention, R⁷ represent —C₁₋₃alkyl. In another aspect ofthe invention, R⁷ represents —CH₃ (methyl).

In one aspect of the invention, R⁸ represents hydrogen. In anotheraspect of the invention, R⁸ represent —C₁₋₃alkyl. In another aspect ofthe invention, R⁸ represents —CH₃ (methyl).

In one aspect of the invention, R⁹ represents morpholine or piperazineoptionally substituted by —C₁₋₆alkyl (such as —CH₃). In another aspectof the invention, R⁹ represents morpholine or piperazine optionallysubstituted by —C₁₋₃alkyl (such as —CH₃). In another aspect of theinvention, R⁹ represents morpholine or piperazine substituted by —CH₃(methyl).

Each of the aspects of the invention are independent unless statedotherwise.

Nevertheless the skilled person will understand that all thepermutations of the aspects of described are within the scope of theinvention. Thus it is to be understood that the present invention coversall combinations of suitable, convenient and exemplified groupsdescribed herein. For example, in one aspect the invention provides acompound of formula (I) wherein X represents —CONH— and R² represents—CH₃.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms). The individualstereoisomers (enantiomers and diastereomers) and mixtures of these areincluded within the scope of the present invention. The invention alsoextends to conformational isomers of compounds of formula

(I) and any geometric (cis and/or trans) isomers of said compounds.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

It will be appreciated that racemic compounds of formula (I) may beoptionally resolved into their individual enantiomers. Such resolutionsmay conveniently be accomplished by standard methods known in the art.For example, a racemic compound of formula (I) may be resolved by chiralpreparative HPLC.

It will also be appreciated that compounds of the invention which existas polymorphs, and mixtures thereof, are within the scope of the presentinvention.

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C₁₋₆alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1,1-dimethylpropyl.However, when a moiety is defined such that alkyl bears a substituent itwill be clear to the skilled person from the context that alkyl mayinclude alkylene, for example methylene (—CH₂—), ethylene (—CH₂CH₂—) andpropylene (—CH₂CH₂CH_(2—).)

As used herein, the term “alkylOH” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms and ahydroxyl group. For example, —C1-6alkylOH means a straight or branchedalkyl containing at least 1, and at most 6, carbon atoms and OH. In oneaspect of the invention, the alkyl chain in —C1-6alkylOH is a straighthydrocarbon chain containing the specified number of carbon atoms and ahydroxyl group.

As used herein, the term “alkoxy” refers to a straight or branchedalkoxy group containing the specified number of carbon atoms. Forexample, C₁₋₆alkoxy means a straight or branched alkoxy group containingat least 1, and at most 6, carbon atoms. Examples of “alkoxy” as usedherein include, but are not limited to, methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy,pentoxy and hexyloxy. The point of attachment may be on the oxygen orcarbon atom. As used herein, the term “halogen” or “halo” refers to afluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo)atom.

As used herein, the term “haloalkyl” refers to an alkyl group having oneor more carbon atoms and wherein at least one hydrogen atom is replacedwith a halogen atom, for example a trifluoromethyl group and the like.

As used herein, the term “cycloalkyl” refers to a saturated cyclic groupcontaining 3 to 6 carbon ring-atoms. Examples include cyclopropyl,cyclopentyl and cyclohexyl.

As used herein, the term “C₅₋₉heteroaryl” refers to an aromatic cyclicgroup containing 5 to 9 ring-atoms 1, 2, 3 or 4 of which arehetero-atoms independently selected from nitrogen, oxygen and sulphurand the remaining ring-atoms are carbon, e.g. isoxazole, oxazole,thiazolopyrimidine, imidazole, thiazole, benzothiazole, thiadiazole,oxadiazole or pyridine and more specifically thiazole, benzothiazole,thiadiazole, oxazole, pyridine and thiazolopyrimidine. This definitionincludes both monocyclic and bicyclic ring systems and bicyclicstructures at least a portion of which is aromatic and the other part issaturated, partially or fully unsaturated.

As used herein, the term ‘—C₆₋₁₀aryl’ means an aromatic carbocyclicmoiety containing 6 to 10 ring-atoms. The definition includes bothmonocyclic and bicyclic ring systems and bicyclic structures at least aportion of which is aromatic and the other part is saturated, partiallyor fully unsaturated. Examples of aromatic, aryl groups include phenyl,naphthyl, anthryl, phenanthryl, indanyl, indenyl, azulenyl, azulanyl,fluorenyl, more specifically phenyl and naphthyl, and more specificallyphenyl.

As used herein, the term “C₆heterocyclyl” refers to a cyclic groupcontaining 6 ring-atoms 1, 2 or 3 of which are hetero-atomsindependently selected from nitrogen, oxygen and sulphur and theremaining ring-atoms are carbon, and, wherein said cyclic group issaturated, partially or fully unsaturated but, which is not aromatic e.g1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine,tetrahydropyran, dihydropyran, 1,3-dioxane, 1,3-dithiane, oxathiane orthiomorpholine and more specifically morpholine and piperazine. Thisdefinition includes bicyclic structures provided the moiety isnon-aromatic.

Examples of heterocyclyl and heteroaryl groups include: furyl, thienyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl,thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, homopiperazinyl,dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl,pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl,azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl,benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl,benzothiazinyl, benzothiophenyl oxazolopyridinyl, benzofuranyl,quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl,benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl andisoindolyl.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

For the avoidance of doubt, the term “independently” means that wheremore than one substituent is selected from a number of possiblesubstituents, those substituents may be the same or different.

As used herein, the term “pharmaceutically acceptable” means a compoundwhich is suitable for pharmaceutical use.

Salts of compounds of formula (I) which are suitable for use in medicineare those wherein the counterion is pharmaceutically acceptable.However, salts having non-pharmaceutically acceptable counterions arewithin the scope of the present invention, for example, for use asintermediates in the preparation of other compounds of formula (I) andtheir pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts will be apparent to thoseskilled in the art and include for example acid addition salts formedwith inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric orphosphoric acid; and organic acids e.g. succinic, maleic, malic,mandelic, acetic, fumaric, glutamic, lactic, citric, tartaric, benzoic,benzenesulfonic, p-toluenesulfonic, methanesulfonic, ethanesulfonic ornaphthalenesulfonic acid. Other non-pharmaceutically acceptable saltse.g. oxalates, may be used, for example in the isolation of compounds offormula (I) and are included within the scope of this invention.Reference is made to Berge et al. J. Pharm. Sci., 1977, 66, 1-19.

Certain of the compounds of formula (I) may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms thereof.

Solvates of the compounds of formula (I) and solvates of the salts ofthe compounds of formula (I) are included within the scope of thepresent invention.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include, but are notlimited to, water, methanol, ethanol and acetic acid. In one aspect ofthe invention, the solvent used is a pharmaceutically acceptablesolvent. In another aspect of the invention, the solvent used is waterand the solvate may also be referred to as a hydrate.

Solvates of compounds of formula (I) which are suitable for use inmedicine are those wherein the solvent is pharmaceutically acceptable.However, solvates having non-pharmaceutically acceptable solvents arewithin the scope of the present invention, for example, for use asintermediates in the preparation of other compounds of formula (I) andtheir pharmaceutically acceptable salts.

Prodrugs of the compounds of formula (I) are included within the scopeof the present invention.

As used herein, the term “prodrug” means a compound which is convertedwithin the body, e.g. by hydrolysis in the blood, into its active formthat has medical effects. Pharmaceutically acceptable prodrugs aredescribed in T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche,ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987 and in D. Fleishner, S. Ramon andH. Barba “Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2)115-130. Prodrugs are any covalently bonded carriers that release acompound of structure (I) in vivo when such prodrug is administered to apatient. Prodrugs are generally prepared by modifying functional groupsin a way such that the modification is cleaved in vivo yielding theparent compound. Prodrugs may include, for example, compounds of thisinvention wherein hydroxyl or amine groups are bonded to any group that,when administered to a patient, cleaves to form the hydroxy or aminegroups. Thus, representative examples of prodrugs include (but are notlimited to) phosphonate, carbamate, acetate, formate and benzoatederivatives of hydroxy and amine functional groups of the compounds offormula (I).

Phosphonates, acetates, benzoates and carbamates may be active in theirown right and/or be hydrolysable under in vivo conditions in the humanbody. Suitable pharmaceutically acceptable in vivo hydrolysable estergroups include those which break down readily in the human body to leavethe parent acid or its salt. A phosphonate is formed by reaction withphosphorous (phosphonic) acid, by methods well known in the art. Forexample, phosphonates may be derivatives such as RP(O)(OR)₂ and thelike. A acetate is an ester of acetic acid. A benzoate is an ester ofbenzenecarboxylic acid. A carbamate is an ester of carbamic acid.

In one aspect of the invention there is provided a compound, or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[6-(methyloxy)-1,3-benzothiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide,-   Ethyl    2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylate,-   Ethyl    5-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3,4-thiadiazole-2-carboxylate,-   Methyl    2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylate,-   1-[(3,4-Dichlorophenyl)methyl]-N-(5-formyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{5-[(methyloxy)methyl]-1,3,4-thiadiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,-   Methyl    {2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazol-4-yl}acetate,-   Ethyl    2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate,-   1-[(3,4-Dichlorophenyl)methyl]-N-(4,5-dimethyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   Ethyl    2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-benzothiazole-6-carboxylate,-   Ethyl    {2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-5-methyl-1,3-thiazol-4-yl}acetate,-   1-[(3,4-Dichlorophenyl)methyl]-N-(5,7-dioxo-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-d]pyrimidin-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   Methyl    6-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-3-pyridinecarboxylate,-   Methyl    2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-pyridinecarboxylate,-   2-[({1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylic    acid,-   2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-oxazole-5-carboxylic    acid,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{4-methyl-5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(4-methyl-5-{[(3-methylbutyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(4-methyl-5-{[(1-methylethypamino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(ethylamino)carbonyl]-4-methyl-1,3-thiazo1-2-yl}-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-[5-({[2-(dimethylamino)ethyl]amino}carbonyl)-4-methyl-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(5-{[(3-methylbutyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[4-methyl-5-(4-morpholinylcarbonyl)-1,3-thiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{4-methyl-5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[4-methyl-5-({[2-(methyloxy)ethyl]amino}carbonyl)-1,3-thiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-4-methyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(dimethylamino)carbonyl]-4-methyl-1,3-thiazol-2-yl}-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(dimethylamino)carbonyl]-1,3-thiazol-2-yl}-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   2-[({1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-N-methyl-4-pyridinecarboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(ethylamino)carbonyl]-4-methyl-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-{4-methyl-5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,-   N-[5-(Aminocarbonyl)-1,3-thiazol-2-yl]-1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide,-   N-[5-(Aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-1,3,4-thiadiazol-2-yl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-5-[(methyloxy)methyl]-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-4-methyl-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   1-[(3,4-Dichlorophenyl)methyl]-N-[4-(hydroxymethyl)-2-pyridinyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,-   N-{1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}-6-(methyloxy)-1,3-benzothiazole-2-carboxamide,    or-   {2-[({1-[(3,4-Dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}methypamino]-1,3-thiazol-5-yl}methanol.

The compounds of the invention have been found to inhibit SCD activityand may therefore be useful in regulating lipid levels, e.g. plasmalipid levels. Diseases or conditions caused by or associated with anabnormal plasma lipid profile and for the treatment of which thecompounds of the invention may be useful include; dyslipidemia,hypoalphalipoproteinemia, hyperbetalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, angina, ischemia, cardiac ischemia, stroke,myocardial infarction, atherosclerosis, obesity, Type I diabetes, TypeII diabetes, insulin resistance, hyperinsulinaemia and metabolicsyndrome. Other cardiovascular diseases for which the compounds of thepresent invention are useful include peripheral vascular disease,reperfusion injury, angioplastic restenosis, hypertension, vascularcomplications of diabetes and thrombosis. Other diseases or conditionsinclude hepatic steatosis, non-alcoholic steatohepatitis (NASH) andother diseases related to accumulation of lipids in the liver.

The compounds of the invention may also be useful in the treatment ofskin disorders e.g. eczema, acne, psoriasis, skin ageing, keloid scarformation or prevention, and diseases related to production orsecretions from mucous membranes.

The compounds of the invention may also be useful in the treatment ofcancer, neoplasia, malignancy, metastases, tumours (benign ormalignant), carcinogenesis, hepatomas and the like.

The compounds of the invention may also be useful in the treatment ofmild cognitive impairment (MCI), Alzheimer's disease (AD), cerebralamyloid angiopathy (CAA) or dementia associated with Down Syndrome (DS)and other neurodegenerative diseases characterized by the formation oraccumulation of amyloid plaques comprising Aβ42.

Within the context of the present invention, the terms describing theindications used herein are classified in the Merck Manual of Diagnosisand Therapy, 17^(th) Edition and/or the International Classification ofDiseases 10^(th) Edition (ICD-10). The various subtypes of the disordersmentioned herein are contemplated as part of the present invention.

In one aspect, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in medical therapy.

In one aspect, the invention provides the use of a compound of formula(I) or a pharmaceutically acceptable salt thereof for the manufacture ofa medicament for treating and/or preventing a disease or a conditionsusceptible to amelioration by an SCD inhibitor.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for treating and/or preventing acne,psoriasis, skin ageing, cancer, dyslipidemia, hypertriglyceridemia,atherosclerosis, obesity, Type II diabetes, insulin resistance,hyperinsulinaemia, hepatic steatosis and/or non-alcoholicsteatohepatitis (NASH).

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for treating and/or preventing acne,psoriasis, skin ageing, cancer, dyslipidemia, atherosclerosis, insulinresistance, hyperinsulinaemia, Type II diabetes and/or hepaticsteatosis.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for treating and/or preventing acne.

In one aspect, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in treating and/orpreventing a disease or a condition susceptible to amelioration by anSCD inhibitor in a mammal, including human.

In another aspect, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in treating and/orpreventing acne, psoriasis, skin ageing, cancer, dyslipidemia,hypertriglyceridemia, atherosclerosis, obesity, Type II diabetes,insulin resistance, hyperinsulinaemia, hepatic steatosis and/ornon-alcoholic steatohepatitis (NASH).

In another aspect, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in treating and/orpreventing acne, psoriasis, skin ageing, cancer, dyslipidemia,atherosclerosis, insulin resistance, hyperinsulinaemia, Type II diabetesand/or hepatic steatosis.

In another aspect, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in treating and/orpreventing acne.

In one aspect, the invention provides a method for treating and/orpreventing a disease or a condition susceptible to amelioration by anSCD inhibitor, which method comprises administering to a subject, forexample a mammal, including human, a therapeutically effective amount ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method for treating and/orpreventing a acne, psoriasis, skin ageing, cancer, dyslipidemia,hypertriglyceridemia, atherosclerosis, obesity, Type II diabetes,insulin resistance, hyperinsulinaemia, hepatic steatosis and/ornon-alcoholic steatohepatitis (NASH), which method comprisesadministering to a subject, for example a mammal, including human, atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method for treating and/orpreventing acne, psoriasis, skin ageing, cancer, dyslipidemia,atherosclerosis, insulin resistance, hyperinsulinaemia, Type II diabetesand/or hepatic steatosis, which method comprises administering to asubject, for example a mammal, including human, a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

In another aspect, the invention provides a method for treating and/orpreventing acne, which method comprises administering to a subject, forexample a mammal, including human, a therapeutically effective amount ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference to “treatment” and “therapy”includes acute treatment or prophylaxis as well as the alleviation ofestablished symptoms.

Since the compounds of the invention are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of theinvention.

Processes for the preparation of the compounds of formula (I) formfurther aspects of the invention. R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ areas defined above unless otherwise specified. Throughout thespecification, general formulae are designated by Roman numerals (I),(II), (III), (IV) etc.

In certain instances final compounds of formula (I) can be convertedinto other compounds of formula (I) by techniques known to those in theart, for example, carboxylic acid substituents can be converted toesters or amides by routine techniques.

In a general process, compounds of formula (I), wherein X represents—CONH— and R³ represents

wherein

represents —C₅₋₉heteroaryl and Y represents —C₁₋₃alkyl, —C₁₋₆alkoxy,—CO₂R⁴, —C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylNR⁷R⁸,—C(═O)NHC₁₋₃alkylOC₁₋₃alkyl, —C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹,—C₁₋₆alkylOH, —C═O, —CHO, —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl,—C₁₋₆haloalkyl, —OC₁₋₆haloalkyl, —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl orhalogen (formula (Ia)), may be prepared according to reaction scheme 1by reacting compounds of formula (II) and compounds of formula (III).The reaction is suitably carried out in the presence of a couplingreagent such as HATU or EDCl and HOBt and a base such as DIPEA or NEt₃in a suitable solvent such as DMF (suitably at room temperature to 40°C.).

Accordingly, in one aspect the invention provides a process for thepreparation of compounds of the formula (Ia) by reacting compounds offormula (II), wherein R¹ and R² are defined above, with compounds offormula (III) wherein

and Y are defined above, in the presence of a coupling agent.

Compounds of formula (II) may be prepared according to reaction scheme 2by reacting compounds of formula (IVa) and compounds of formula (IVb).The reaction is suitably carried out in the presence of base such aspotassium carbonate in a suitable solvent such as DMF or DMSO (suitablyat 40-80° C.) and is followed by saponification of compounds of formula(IV) in basic conditions such as sodium hydroxide in a suitable solventsuch as ethanol or methanol (to reflux).

Compounds of formula (II), wherein R² represents H (formula (IIa)), maybe prepared according to reaction scheme 3 by reacting compounds offormula (IVa) and ethyl 2-propynoate in a suitable solvent such asethanol to reflux and is followed by saponification of compounds offormula (V) in basic conditions such as sodium hydroxide in a suitablesolvent such as ethanol or methanol (suitably at reflux).

Compounds of formula (IVa) may be prepared according to reaction scheme4 by the reaction of benzyl halide chlorine or bromine (VI) with sodiumazide in a suitable solvent such as DMSO or DMF (suitably at roomtemperature to 80° C.).

Compounds of formula (I), wherein X represents —NHCO— and R³ represents

wherein

and Y are defined as above (formula (Ib)), may be prepared according toreaction scheme 5 by reacting compounds of formula (VII) and compoundsof formula (VIII). The reaction is suitably carried out in the presenceof a coupling reagent such as HATU and a base such as DIPEA in asuitable solvent such as DCM or DMF (suitably at room temperature to 40°C.).

Accordingly, in another aspect the invention provides a process for thepreparation of compounds of the formula (Ib) by reacting compounds offormula (VII), wherein R¹ and R² are defined above, with compounds offormula (VIII) wherein

and Y are defined above, in the presence of a coupling reagent.

Compounds of formula (VII), wherein R² represents H, —C₁₋₆alkyl or—C₁₋₃alkylOC₁₋₃alkyl, (formula (VIIa)), may be prepared according toreaction scheme 6 by reacting compounds of formula (VIIb) in thepresence of bromine and a base such as potassium hydroxide in a suitablesolvent such as water (suitably at 40° to 80° C.).

Compounds of formula (VIIb), wherein R² represents H, —C₁₋₆alkyl or—C₁₋₃alkylOC₁₋₃alkyl may be prepared according to reaction scheme 7 byreacting compounds of formula (II), wherein R² represents —CH₃ (formula(IIb), in the presence of thionyl chloride in chloroform at roomtemperature, followed by reaction with aqueous ammonia in acetonitrileon ice (e.g. −5 to 5° C.).

Compounds of formula (I), wherein R³ represents

is defined as above (formula (Ic)), may be prepared according toreaction scheme 8 by reduction of the ester function (—COOR⁴) ofcompounds of the formula (IX) in the presence of DIBAL-H in a solutionof toluene. The reaction is suitably carried out in a solvent such asTHF at room temperature.

Accordingly, in another aspect the invention provides a process for thepreparation of compounds of the formula (Ic) by reduction of the esterfunction (—COOR⁴) of compounds of the formula (IX) wherein R¹, R² and

are defined above.

Compounds of formula (I), wherein R³ represents

is defined as above (formula (Ic)), may also be prepared according toreaction scheme 9 by reduction of the aldehyde function (—CHO) ofcompounds of the formula (X) in the presence of sodium borohydride in asuitable solvent such as DCM/MeOH at room temperature.

Accordingly, in another aspect the invention provides a process for thepreparation of compounds of the formula (Ic) by reduction of thealdehyde function (—CHO) of compounds of the formula (VIIIa) wherein R¹,R² and

are defined above.

Compounds of formula (I), wherein R³ represents

is defined as above (formula (Id)), may be prepared according toreaction scheme 10 by saponification of the ester function (—COOR⁴) ofcompounds of the formula (IXa) in basic conditions in a suitable solventsuch as methanol or ethanol at reflux.

Accordingly, in another aspect the invention provides a process for thepreparation of compounds of the formula (Id) by saponification of theester function (—COOR⁴) of compounds of the formula (IXa) wherein R¹, R²and

are defined above.

Compounds of formula (I), wherein R³ represents

is defined as above (formula (Ie)), may be prepared according toreaction scheme 11 by reacting compounds of formula (Id), wherein

is defined as above, and compounds of formula (XI), wherein R represents—R⁵R⁶, —C₁₋₃alkylNR⁷R⁸, —C₁₋₃alkylOC₁₋₃alkyl or —C₁₋₃alkylOH in thepresence of a coupling reagent such as HATU and base such as DIPEA in asuitable solvent such as DMF (suitably at room temperature or at 40°C.).

Accordingly, in another aspect the invention provides a process for thepreparation of compounds of the formula (Ie) by reacting compounds ofthe formula (Id), wherein R¹, R² and

are defined above, with compounds of the formula (XI) wherein R isdefined above, in the presence of a coupling agent.

Compounds of formula (I), wherein X represents —CH₂N— and R³ represents

wherein

and Y are defined as above, (formula (If)), may be prepared according toreaction scheme 12 by reacting compounds of formula (XII) and compoundsof formula (III) in the presence of a base such as potassium carbonatein a suitable solvent such as acetonitrile suitably at 40° C.

Accordingly, in another aspect the invention provides a process for thepreparation of compounds of the formula (If) by reacting compounds ofthe formula (XIII), wherein R¹ and R² are defined above, with compoundsof the formula (III) wherein

and Y are defined above, in the presence of a base.

Compounds of formula (XII) may be prepared according to reaction scheme13 by the reduction of compounds of formula (IV) using DIBAL in asuitable solvent such as THF to room temperature to give the compound(XIII), followed by the bromination of compounds of the formula (XII)with PBr₃ in a suitable solvent such as dichloromethane suitably at roomtemperature.

Compounds of the formula (III), (IVb) (VI), (VIII) and (XI) arecommercially available compounds or may be prepared by methods known inthe literature or processes known to those skilled in the art.

Compounds of the formula (IX), (IXa) and (X) may be prepared accordingto the general reaction scheme 1.

Further details for the preparation of compounds of formula (I) arefound in the examples section hereinafter.

The compounds of the invention may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, andmore preferably 10 to 100 compounds. Libraries of compounds of theinvention may be prepared by a combinatorial ‘split and mix’ approach orby multiple parallel syntheses using either solution phase or solidphase chemistry, by procedures known to those skilled in the art. Thusaccording to a further aspect there is provided a compound librarycomprising at least 2 compounds of the invention.

Those skilled in the art will appreciate that in the preparation ofcompounds of formula (I) and/or salts thereof it may be necessary and/ordesirable to protect one or more sensitive groups in the molecule or theappropriate intermediate to prevent undesirable side reactions. Suitableprotecting groups for use according to the present invention are wellknown to those skilled in the art and may be used in a conventionalmanner. See, for example, “Protective groups in organic synthesis” by T.W. Greene and P. G. M. Wuts (John Wiley & sons 1991) or “ProtectingGroups” by P. J. Kocienski (Georg Thieme Verlag 1994). Examples ofsuitable amino protecting groups include acyl type protecting groups(e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane typeprotecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz),aliphatic urethane protecting groups (e.g. 9-fl uorenylmethoxycarbonyl(Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl,cyclohexyloxycarbonyl) and alkyl or aralkyl type protecting groups (e.g.benzyl, trityl, chlorotrityl).

Various intermediate compounds used in the above-mentioned process,including but not limited to certain compounds of formulae (II), (V),constitute a further aspect of the present invention.

The compounds of formula (I) or pharmaceutically acceptable salt(s)thereof may also be used in combination with other therapeutic agents.The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or pharmaceutically acceptable saltthereof together with one or more further therapeutic agent(s).

Compounds of the invention may be administered in combination with othertherapeutic agents. Preferred therapeutic agents are selected from thelist: an inhibitor of cholesteryl ester transferase (CETP inhibitors), aHMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein,a peroxisome proliferator-activated receptor activator (PPAR), a bileacid reuptake inhibitor, a cholesterol absorption inhibitor, acholesterol synthesis inhibitor, a fibrate, niacin, an ion-exchangeresin, an antioxidant, an inhibitor of AcylCoA: cholesterolacyltransferase (ACAT inhibitor), a cannabinoid 1 antagonist and a bileacid sequestrant. Other preferred therapeutic agents are selected fromthe list a corticosteroid, a vitamin D3 derivative, a retinoid, animmunomodulator, an anti androgen, a keratolytic agent, ananti-microbial, a platinum chemotherapeutic, an antimetabolite,hydroxyurea, a taxane, a mitotic disrupter, an anthracycline,dactinomycin, an alkylating agent and a cholinesterase inhibitor.

When the compound of formula (I) or pharmaceutically acceptable saltthereof is used in combination with a second therapeutic agent the doseof each compound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart. It will be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with atleast one pharmaceutically acceptable carrier and/or excipient comprisea further aspect of the invention. The individual components of suchcombinations may be administered either sequentially or simultaneouslyin separate or combined pharmaceutical formulations by any convenientroute.

When administration is sequential, either the SCD inhibitor or thesecond therapeutic agent may be administered first. When administrationis simultaneous, the combination may be administered either in the sameor different pharmaceutical composition.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

The invention also includes a pharmaceutical composition comprising oneor more compounds of formula (I) or pharmaceutically acceptable salt (s)in combination with one or more excipients.

The compounds of the invention may be administered in conventionaldosage forms prepared by combining a compound of the invention withstandard pharmaceutical carriers or diluents according to conventionalprocedures well known in the art. These procedures may involve mixing,granulating and compressing or dissolving the ingredients as appropriateto the desired preparation.

The pharmaceutical compositions of the invention may be formulated foradministration by any route, and include those in a form adapted fororal, topical or parenteral administration to mammals including humans.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, creams or liquid preparations, such as oral orsterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, dispersions, lotions, creams, gels, pastes, powders,aerosol sprays, syrups or ointments on sponges or cotton applicators,and solutions or suspensions in an aqueous liquid, non-aqueous liquid,oil-in-water emulsion, or water-in-oil liquid emulsion.

Creams, lotions, or ointments, may be prepared as rinse-off or leave-onproducts, as well as two stage treatment products for use with otherskin cleansing or managing compositions. The compositions can beadministered as a rinse-off product in a higher concentration form, suchas a gel, and then a leave-on product in a lower concentration to avoidirritation of the skin. Each of these forms is well understood by thoseof ordinary skill in the art, such that dosages may be easily preparedto incorporate the pharmaceutical composition of the invention.

Ointments are hydrocarbon-based semisolid formulations containingdissolved or suspended drugs. Creams and lotions are semi-solid emulsionsystems and the term is applied both to water/oil or oil/water. Gelformulations are semi-solid systems in which a liquid phase is trappedin a polymeric matrix.

By way of non-limiting example, the ointments may contain one or morehydrophobic carriers selected from, for example, white soft paraffin orother mineral waxes, liquid paraffin, non-mineral waxes, long chainalcohols, long chain acids and silicones. The ointment may contain inaddition to the hydrophobic carriers some hydrophillic carriers selectedfrom, for example, propylene glycol and polyethylene glycol incombination with an appropriate surfactant/co-surfactant system. Thecarrier compositions of the creams or lotions are typically based onwater, white soft paraffin and an appropriate surfactant/co-surfactantsystem, in combination with other carriers/components selected from, forexample, propylene glycol, butylene glycol glycerinemonostearate,PEG-glycerinemonostearate, esters such as C₁₂₋₁₅ alkyl benzoate, liquidparaffin, non-mineral waxes, long chain alcohols, long chain acidssilicones, non-silicone polymers. The gels may by way of example beformulated using isopropyl alcohol or ethyl alcohol, propylene glycoland water with a gelling agent such as hydroxyethyl cellulose, suitablyin combination with minor components, for example one or more ofbutylene glycol and a wetting agent such as a poloxamer.

An ointment, cream, lotion, gel, and the like, can further comprise amoisturizing agent. The moisturizing agent can be a hydrophobicmoisturizing agent such as ceramide, borage oil, tocopherol, tocopherollinoleate, dimethicone or a mixture thereof or a hydrophilicmoisturizing agent such as glycerine, hyaluronic acid, sodiumperoxylinecarbolic acid, wheat protein, hair keratin amino acids, or amixture thereof.

The compositions according to the invention may also compriseconventional additives and adjuvants for dermatological applications,such as preservatives, acids or bases used as pH buffer excipients andantioxidants.

The present invention encompasses administration via a transdermal patchor other forms of transdermal administration. Suitable formulations fortransdermal administration are known in the art, and may be employed inthe methods of the present invention. For example, suitable transdermalpatch formulations for the administration of a pharmaceutical compoundare described in, for example, U.S. Pat. No. 4,460,372 to Campbell etal., U.S. Pat. No. 4,573,996 to Kwiatek et al., U. S. Pat. No. 4,624,665to Nuwayser, U.S. Pat. No. 4,722,941 to Eckert et al., and U.S. Pat. No.5, 223,261 to Nelson et al.

One suitable type of transdermal patch for use in the methods of thepresent invention encompasses a suitable transdermal patch includes abacking layer which is non-permeable, a permeable surface layer, anadhesive layer substantially continuously coating the permeable surfacelayer, and a reservoir located or sandwiched between the backing layerand the permeable surface layer such that the backing layer extendsaround the sides of the reservoir and is joined to the permeable surfacelayer at the edges of the permeable surface layer. The reservoircontains a compound of formula (I) or pharmaceutically acceptable saltthereof, alone or in combination, and is in fluid contact with thepermeable surface layer. The transdermal patch is adhered to the skin bythe adhesive layer on the permeable surface layer, such that thepermeable surface layer is in substantially continuous contact with theskin when the transdermal patch is adhered to the skin. While thetransdermal patch is adhered to the skin of the subject, the compound offormula (I) or pharmaceutically acceptable salt thereof contained in thereservoir of the transdermal patch is transferred via the permeablesurface layer, from the reservoir, through the adhesive layer, and tothe skin of the patient. The transdermal patch may optionally alsoinclude one or more penetration-enhancing agents in the reservoir thatenhance the penetration of the compound of formula (I) orpharmaceutically acceptable salt thereof through the skin.

Examples of suitable materials which may comprise the backing layer arewell known in the art of transdermal patch delivery, and anyconventional backing layer material may be employed in the transdermalpatch of the instant invention.

Suitable penetration-enhancing agents are well known in the art as well.Examples of conventional penetration-enhancing agents include alkanolssuch as ethanol, hexanol, cyclohexanol, and the like, hydrocarbons suchas hexane, cyclohexaue, isopropylbenzene; aldebydes and ketones such ascyclohexanone, acetamide, N,N-di(lower alkyl)acetamides such asN,N-diethylacetamide, N,N-dimethyl acetamide,N-(2-hydroxyethyl)acetamide, esters such as N,N-di-lower alkylsulfoxides; essential oils such as propylene glycol, glycerine, glycerolmonolaurate, isopropyl myristate, and ethyl oleate, salicylates, andmixtures of any of the above.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Preparations for oral administration may be suitably formulated to givecontrolled/extended release of the active compound.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilising the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilised powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active ingredient, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

It will be recognised by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of theinvention will be determined by the nature and extent of the conditionbeing treated, the form, route and site of administration, and theparticular mammal being treated, and that such optimums can bedetermined by conventional techniques. It will also be appreciated byone of skill in the art that the optimal course of treatment, i.e., thenumber of doses of a compound of the invention given per day for adefined number of days, can be ascertained by those skilled in the artusing conventional course of treatment determination tests.

The invention also extends to novel intermediates disclosed herein, usedin the preparation of compounds of formula (I) or salts thereof.

The following is a list of the used definitions:

DEFINITIONS

-   APTS Para toluene sulfonic acid-   DCM Dichloromethane-   DIBAL Diisobutylaluminium hydride solution-   DIPEA Diisopropyl ethyl amine-   DME 1,2-Dimethoxy ethane-   DMF Dimethylformamide-   DMSO Dimethyl sulfoxide-   EDCl 1,3-Propanediamine N₃-(ethylcarbonimidoyl)-N₁,N₁-dimethyl-,    hydrochloride-   EtOH Ethanol-   HATU O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HCl Hydrochloric acid-   HOBt Hydroxy benzotriazole-   NaOH Sodium hydroxide-   NEt₃ Triethylamine-   NH₄Cl Ammonium chloride-   PBr₃ Phosphorus tribromine-   Pd tetrakis Tetrakis(triphenylphosphine)palladium (0)-   Pd/C Palladium (0) on carbon-   THF Tetrahydrofuran

Regardless of how the preparation of compounds are represented in thepresent specification no inference can be drawn that particular batches(or mixtures of two or more batches) of intermediates were used in thenext stage of the preparation. The examples and intermediates areintended to illustrate the synthetic routes suitable for preparation ofthe same, to assist the skilled persons understanding of the presentinvention.

Where reference is made to the use of a “similar” procedure, as will beappreciated by those skilled in the art, such a procedure may involveminor variation, for example reaction temperature, reagent/solventamount, reaction time, work-up conditions or chromatographicpurification conditions.

Analytical Methods LC-MS

Analytical HPLC was conducted on a X-terra MS C18 column (2.5 μm 3*30 mmid) eluting with 0.01 M ammonium acetate in water (solvent A) and 100%acetonitrile using the following elution gradient: 0 to 4 minutes, 5 to100% B; 4 to 5 minutes, 100% B at a flowrate of 1.1 mL/min with atemperature of 40° C.

The mass spectra (MS) were recorded on a micromass ZQ-LC massspectrometer using electrospray positive ionisation [ES+ve to give MH⁺molecular ion] or electrospray negative ionisation [ES−ve to give (M−H)⁻molecular ion] modes.

Analytical Methods LC-HRMS

Analytical HPLC was conducted on an Uptisphere-hsc column (3 μm 30*3 mmid) eluting with 0.01M ammonium acetate in water (solvent A) and 100%acetonitrile (solvent B) using the following elution gradient: 0 to 0.5minutes, 5% B; 0.5 to 3.5 minutes, 5 to 100% B; 3.5 to 4 minutes, 100%B; 4 to 4.5 minutes, 100 to 5% B; 4.5 to 5.5 minutes, 5% B at a flowrateof 1.3 mL/min with a temperature of 40° C.

The mass spectra (MS) were recorded on a micromass LCT, massspectrometer using electrospray positive ionisation [ES+ve to give MH⁺molecular ion] or electrospray negative ionisation [ES-ve to give (M−H)⁻molecular ion] modes.

Analytical method GC-MS

Analytical GC was conducted on a DB-1ms column (Agilent Technologies),0.1 μm 10 m*0.1 mm id) eluting with an Helium flow of 0.5m1/min andpressure at 3.4 bar and with a gradient temperature: 0 to 0.35 min, 100°C.; 0.35 min to 6 min, 100° C. to 250° C. (ramp of 80° C/min).

The mass spectra (MS) were recorded on a Agilent Technologies G5973 massspectrometer using electronic impact ionisation.

SUPPORTING EXAMPLES AND INTERMEDIATES

The invention is illustrated by the non-limiting Examples describedbelow.

Intermediate 1 (3,4-Dichlorophenyl)methyl Azide

A mixture of 3,4-dichlorobenzyl chloride (10 g, 0.05 mol), sodium azide(5 g, 0.08 mol) in DMSO (100 mL) was stirred at room temperatureovernight. The mixture was poured into water (150 mL). The water layerwas extracted with EtOAc (100 ml×3). The combined organic phases weredried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by distillation to give the title compound as anoil (14 g, quantitative yield). LC/MS: m/z 203 (M+H)⁺. Rt: 2.26 min.

Intermediate 2 Methyl1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylate

To a suspension of milled potassium carbonate (38.7 g, 0.28 mol) in DMSO(100 mL) was added Intermediate 1 (14 g, 0.07 mol) and methylacetoacetate (12.1 g, 0.1 mol). The mixture was stirred at 40° C. for 2days. The mixture was poured into a mixture of ice and water (100 mL).The water was extracted with ethyl acetate (100 mL×2). The combinedorganic phases were dried over sodium sulfate, filtered andconcentrated. The residue was purified by distillation to give the titlecompound as white solid crystals (14 g, 67%). LC/MS: m/z 301 (M+H)⁺. Rt:1.97 min.

The following compounds were similarly prepared by a method analogous tothat described for Intermediate 2:

TABLE 1 Physical Compound Structure From data Intermediate 3 Methyl1-[(3,4- dichlorophenyl)methyl]-5- [(methyloxy)methyl]-1H-1,2,3-triazole-4- carboxylate

(3,4-Dichlorophenyl) methyl azide (Intermediate 1) and Ethyl4-(methyloxy)-3- oxobutanoate LC/MS: m/z 330 (M + H)⁺, Rt: 3.12 min

Intermediate 41-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylicAcid

To a mixture of methyl1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylate(Intermediate 2) (9 g, 0.03 mol) in methanol (200 mL) was added NaOH(2.4 g) and water. The mixture was stirred overnight. Water was addedand the solvent was evaporated. The residue was extracted with DCM(twice). The aqueous phase was adjusted to pH=2 with a 2N HCl solution.The formed precipitate was filtered to give the title compound as whitesolid (7.2 g, 84%). LC/MS: m/z 287 (M+H)⁺. Rt: 2.52 min.

The following compounds were similarly prepared by a method analogous tothat described for Intermediate 4:

TABLE 2 Physical Compound Structure From data Intermediate 5 1-[(3,4-Dichlorophenyl) methyl]-5- [(methyloxy)methyl]- 1H-1,2,3-triazole-4-carboxylic acid

Methyl 1-[(3,4- dichlorophenyl) methyl]-5- [(methyloxy)methyl]-1H-1,2,3-triazole-4- carboxylate (Intermediate 3) LC/MS: m/z 316 (M +H)⁺, Rt: 2.22 min

Intermediate 62-[({1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylicAcid

A mixture of methyl2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylate(Example 4) (0.403 g, 0.95 mmol) and a 1N NaOH solution (10 mL, 9.5mmol) in EtOH was stirred at reflux for 2 hours. The solvent wasevaporated and the residue was acidified with a 1N HCl solution. Theprecipitate formed was filtered and dried to give the title compound asa white solid (326 mg, 83%). LC/MS: m/z 412 (M+H)⁺. Rt: 2.48 min.

The following compounds were similarly prepared by a method analogous tothat described for Intermediate 6:

TABLE 3 Physical Compound. Structure From data Intermediate 72-[({1-[(3,4- Dichlorophenyl)methyl]- 5-methyl-1H-1,2,3- triazol-4-yl}carbonyl)amino]-4- pyridinecarboxylic acid

Methyl 2-[({1-[(3,4- dichlorophenyl) methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl)amino]-4- pyridinecarboxylate (Example 15)LC/MS: m/z 406 (M + H)⁺, Rt: 2.47 min

Intermediate 8 Ethyl2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-oxazole-5-carboxylate

A mixture of1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylicacid (Intermediate 4) (1 g, 3.4 mmol), ethyl2-amino-1,3-oxazole-5-carboxylate (0.82 g, 5.2 mmol), HOBt (0.708 g, 5.2mmol), EDCl (1.005 g, 5.2 mmol) and NEt₃ (730 μL, 5.2 mmol) in DMF (50mL) was stirred at room temperature for 2 days. The reaction was notcompleted and 2.5 eq of EDCl and HOBt were added and the reaction washeated at 40° C. and stirred for a further 14 days. Again no completedreaction was obtained. The solvent was evaporated and the residue waswashed with water and extracted with DCM. The organic phase was driedover sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography eluting with DCM/MeOH (90/10) togive after crystallisation from diisopropyl ether, the title compound asa yellow solid (98 mg, 6%). LC/MS: m/z 424 (M+H)⁺. Rt: 3.17 min.

The following compounds were similarly prepared by a method analogous tothat described for Intermediate 8:

TABLE 4 Physical Compound Structure From data Intermediate 9 1-[(3,4-dichlorophenyl) methyl]-N-(5-formyl- 1,3-thiazol-2-yl)-5-[(methyloxy)methyl]- 1H-1,2,3-triazole-4- carboxamide

1-[(3,4- Dichlorophenyl)methyl]- 5-[(methyloxy)methyl]-1H-1,2,3-triazole-4- carboxylic acid (Intermediate 5) and 2-amino-1,3-thiazole-5-carbaldehyde LC/MS: m/z 426 (M + H)⁺, Rt: 3.15 min

Intermediate 10 Ethyl1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylate

To a solution of 4-(bromomethyl)-1,2-dichlorobenzene (2 g, 8.3 mmol), inDMF (30 mL) was added sodium azide (0.65 g, 1.2 eq). The reaction wasstirred at 80° C. for 3 hours. The solvent was then evaporated and theresidue was dissolved in DCM and washed with water. The organic phasewas dried over sodium sulphate and the solvent was evaporated. The crudeazido compound was dissolved in ethanol (100 mL) and ethyl 2-propynoate(1 mL, 1.2 eq) was added. The reaction was stirred to reflux for 24hours. The reaction was not completed and 0.3 mL of ethyl 2-propynoatewas added and the reaction was stirred to refleux for more 24 hours.Ethanol was evaporated and the reaction was dissolved in DCM and washedwith water, dried over sodium sulphate and concentrated in vacuo.Purification by flash chromatography eluting with DCM and DCM/MeOH 99/1gave the title compound as a white solid (1.5 g, 60%). LC/MS: m/z 300(M+H)⁺. Rt: 3.12 min.

Intermediate 111-[(3,4-Dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylic Acid

A solution of ethyl1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylate(Intermediate 10) (1.5 g, 5 mmol) and a 1N NaOH solution (7.5 mL, 1.5eq) in ethanol (50 mL) was stirred at reflux for 48 hours. The solventwas evaporated and the residue was acidified with a 1N HCl solution (15mL). The precipitate formed was filtered, washed with water and dried togive the title compound as a white solid (1.25 g, 92%). LC/MS: m/z 272(M+H)⁺. Rt: 2.05 min.

Intermediate 12 Methyl2-[({1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylate

A mixture of1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylic acid(Intermediate 11) (1 g, 3.6 mmol), methyl2-amino-1,3-thiazole-5-carboxylate (0.58 g, 3.6 mmol), HATU (1.82 g, 1.3eq) and DIPEA (0.9 mL, 1.3 eq) in DMF (50 mL) was stirred at 40° C. for3 days. The solvent was evaporated and the residue was washed with waterand extracted with DCM. A precipitate was formed, filtered andtriturated with a mixture of methanol/acetonitrile. After filtration,the yellow solid was dried to give the title compound as a pale yellowsolid (644 mg, 44%). LC/MS: m/z 412 (M+H)⁺. Rt: 3.21 min.

The following compounds were similarly prepared by a method analogous tothat described for Intermediate 12:

TABLE 5 Physical Compound Structure From data Intermediate 13 Ethyl2-[({1-[(3,4- dichlorophenyl)methyl]- 1H-1,2,3-triazol-4-yl}carbonyl)amino]-4- methyl-1,3-thiazole-5- carboxylate

1-[(3,4- Dichlorophenyl) methyl]-1H-1,2,3- triazole-4-carboxylic acid(Intermediate 11) and Ethyl 2-amino-4- methylthiazole-5- carboxylateLC/MS: m/z 438 (M − H)⁺ Rt: 3.55 min

Intermediate 142-[({1-[(3,4-Dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylicAcid

A solution of methyl2-[({1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylate(Intermediate 12) (0.644 g, 1.6 mmol) and a 1N NaOH solution (4.7 mL, 3eq) in ethanol (40 mL) was stirred at reflux for 3 days. The solvent wasevaporated and the residue was acidified with a 1N HCl solution (5 mL).The precipitate formed was filtered, washed with water and dried to givethe title compound as a white solid (0.19 g, 30.5%). The filtratecontained a large quantity of the title compound. LC/MS: m/z 398 (M+H)⁺.Rt: 2.35 min.

The following compounds were similarly prepared by a method analogous tothat described for Intermediate 14:

TABLE 6 Physical Compound Structure From data Intermediate 152-[({1-[(3,4- dichlorophenyl)methyl]- 1H-1,2,3-triazol-4-yl}carbonyl)amino]-4- methyl-1,3-thiazole-5- carboxylic acid

Ethyl 2-[({1-[(3,4- dichlorophenyl) methyl]-1H-1,2,3-triazol-4-yl}carbonyl) amino]-4-methyl- 1,3-thiazole-5- carboxylate(Intermediate 13) LC/MS: m/z 412 (M + H)⁺, Rt: 2.41 min

Intermediate 16{1-[(3,4-Dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}methanol

To a solution of ethyl1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylate(Intermediate 10) (0.33 g, 1.09 mmol) in THF was added a 1M solution ofDIBAL-H in toluene (2.3 mL, 2.1 eq) and the reaction was stirred at roomtemperature for 2 hours. The reaction was not completed. Two moreequivalents of a 1M solution of DIBAL-H in toluene were added and thereaction was stirred for a further 18 hours. Solid NH₄Cl was addedfollowed by water and the aqueous phase was extracted with ether, ethylacetate, dried over sodium sulphate and evaporated. The title compoundwas obtained as a white powder after recrystallisation from isopropylether (170 mg, 60%). LC/MS: m/z 258 (M+H)⁺ Rt: 2.45 min.

Intermediate 174-(Bromomethyl)-1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole

To a solution of{1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}methanol(Intermediate 16) (0.17 g, 0.66 mmol) in DCM was added PBr₃ (125 μL, 2eq) and the reaction was stirred at room temperature for 3 hours. Waterwas added, followed by solid NaHCO₃. The organic phase was dried oversodium sulphate and evaporated. The title compound was obtained as acolorless oil (0.21 g, 99%) and used in the next step withoutpurification. LC/MS: m/z 320 (M-H)⁺. Rt: 2.13 min.

Intermediate 181-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide

To a solution of(1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylicacid) Intermediate 4 (14 g, 48.9 mmol), in chloroform (200 mL) was addedthionyl chloride (30 mL) at room temperature. The reaction mixture wasstirred to reflux for 4 hours and concentrated in vacuum. The mixturewas then dissolved in acetonitrile (50 mL) and aqueous ammonia (50 mL)was added at 0° C. for 30 min.The resulting solid was filtered and driedto give the title compound as white crystals. (12.7 g, 91.1%). LC/MS:m/z 285 (M+H)⁺. Rt: 2.53 min.

Intermediate 191-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-amine

To a solution of potassium hydroxide (10.96 g, 195.8 mmol) in water (50mL), cooled in an ice-salt bath, was added bromine (6.3 g, 39.16 mmol)and at 0° C.,1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide(Intermediate 18) (9.3 g, 32.63 mmol) was added for 4 hours undervigorous stirring. The reaction mixture was then warmed at 80° C. for 2days and stirred at room temperature for 12 hours. The resulting solidwas filtered and purified by HPLC to give the title compound (3.45 g,41.14%). LC/MS: m/z 257 (M+H)⁺. Rt: 2.25 min.

Example 11-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[6-(methyloxy)-1,3-benzothiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide

A mixture of1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylicacid (Intermediate 4) (0.1 g, 0.35 mmol), 2-amino-6-methoxybenzothiazole(0.062 g, 0.35 mmol), HATU (0.082 g, 0.45 mmol) and DIPEA (85 μL, 0.45mmol) in DMF (5 mL) was stirred at 45° C. for 3 days. The solvent wasevaporated and the residue was washed with water and extracted with DCM.The organic phase was dried over sodium sulphate, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with DCM/MeOH (99/1) to give after trituration in diisopropylether, the title compound as a white solid (15 mg, 10%). HRMS calculatedfor C₁₉H₁₅Cl₂N₅O₂S (M+H)⁺ 448.0402, found: 448.0403, Rt: 3.31 min. MP:225° C.

The following compounds were similarly prepared by a method analogous tothat described for Example 1:

TABLE 7 Compound Structure From Physical data Example 2 Ethyl2-[({1-[(3,4- dichlorophenyl) methyl]-5-methyl-1H- 1,2,3-triazol-4-yl}carbonyl)amino]-4- methyl-1,3-thiazole-5- carboxylate

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and ethyl 2-amino-4- methylthiazole-5-carboxylate HRMS calculated for C₁₈H₁₇Cl₂N₅O₃S Theo: 454.0507 Found:454.0539 Rt: 3.34 min Example 3 Ethyl 5-[({1-[(3,4- dichlorophenyl)methyl]-5-methyl-1H- 1,2,3-triazol-4- yl}carbonyl)amino]-1,3,4-thiadiazole-2- carboxylate

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-carboxylic acid (Intermediate 4) and 5-amino-1,3,4- thiadiazole-2-carboxylic acid ethyl ester HRMS calculated for C₁₆H₁₄Cl₂N₆O₃S Theo:441.0303 Found: 441.0278 Rt: 2.80 min MP: 203.8° C. Example 4 Methyl2-[({1-[(3,4- dichlorophenyl) methyl]-5-methyl-1H- 1,2,3-triazol-4-yl}carbonyl)amino]- 1,3-thiazole-5- carboxylate

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and methyl 2- aminothiazole-5-carboxylate HRMS calculated for C₁₆H₁₃Cl₂N₅O₃S Theo: 426.0194 Found:426.0222 Rt: 3.03 min MP: 212° C. Example 5 1-[(3,4- Dichlorophenyl)methyl]-N-(5-formyl- 1,3-thiazol-2-yl)-5- methyl-1H-1,2,3- triazole-4-carboxamide

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and 2-amino-1,3- thiazole-5-carbaldehyde HRMS calculated for C₁₅H₁₁Cl₂N₅O₂S Theo: 396.0089 Found:396.0103 Rt: 2.86 min MP > 260° C. Example 6 1-[(3,4- Dichlorophenyl)methyl]-5-methyl-N- (5-methyl-1,3,4- oxadiazol-2-yl)-1H-1,2,3-triazole-4- carboxamide

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and 5-methyl-1,3,4- oxadiazol-2-amineHRMS calculated for C₁₄H₁₂Cl₂N₆O₂ Theo: 367.0477 Found: 367.0500 Rt:2.46 min MP: 192.2° C. Example 7 1-[(3,4- Dichlorophenyl)methyl]-5-methyl-N- {5- [(methyloxy)methyl]- 1,3,4-thiadiazol-2-yl}-1H-1,2,3-triazole-4- carboxamide

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and 5- [(methyloxy)methyl]-1,3,4-thiadiazol-2- amine HRMS calculated for C₁₅H₁₄Cl₂N₆O₂S Theo:413.0354 Found: 413.0363 Rt: 2.79 min MP: 178.3° C. Example 8 Methyl{2-[({1-[(3,4- dichlorophenyl) methyl]-5-methyl-1H- 1,2,3-triazol-4-yl}carbonyl)amino]- 1,3-thiazol-4- yl}acetate

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and methyl (2-amino- 1,3-thiazol-4-yl)acetate HRMS calculated for C₁₇H₁₅Cl₂N₅O₃S Theo: 440.0351 Found:440.0373 Rt: 2.96 min MP: 158° C. Example 9 Ethyl 2-[({1-[(3,4-dichlorophenyl) methyl]-5-methyl-1H- 1,2,3-triazol-4-yl}carbonyl)amino]-4- (trifluoromethyl)-1,3- thiazole-5- carboxylate

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and ethyl 2-amino-4-(trifluoromethyl)-1,3- thiazole-5- carboxylate HRMS calculated forC₁₈H₁₄Cl₂F₃N₅O₃S Theo: 508.0225 Found: 508.0252 Rt: 3.5 min MP: 155° C.Example 10 1-[(3,4- Dichlorophenyl) methyl]-N-(4,5-dimethyl-1,3-thiazol- 2-yl)-5-methyl-1H- 1,2,3-triazole-4- carboxamide

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and 4,5-dimethyl-1,3- thiazol-2-amineHRMS calculated for C₁₆H₁₅Cl₂N₅OS Theo: 396.0453 Found: 396.0464 Rt:3.19 min MP: 210.4° C. Example 11 Ethyl 2-[({1-[(3,4- dichlorophenyl)methyl]-5-methyl-1H- 1,2,3-triazol-4- yl}carbonyl)amino]-1,3-benzothiazole-6- carboxylate

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and ethyl 2-amino-1,3- benzothiazole-6-carboxylate HRMS calculated for C₂₁H₁₇Cl₂N₅O₃S Theo: 490.0507 Found:490.0527 Rt: 3.49 min MP: 199° C. Example 12 Ethyl {2-[({1-[(3,4-dichlorophenyl)methyl]- 5-methyl-1H-1,2,3- triazol-4-yl}carbonyl)amino]-5- methyl-1,3-thiazol-4- yl}acetate

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and ethyl (2-amino-5-methyl-1,3-thiazol-4- yl)acetate HRMS calculated for C₁₉H₁₉Cl₂N₅O₃STheo: 468.0664 Found: 468.0685 Rt: 3.2 min MP: 125° C. Example 131-[(3,4- Dichlorophenyl) methyl]-N-(5,7-dioxo- 4,5,6,7-tetrahydro[1,3]thiazolo [4,5-d]pyrimidin-2- yl)-5-methyl-1H-1,2,3-triazole-4- carboxamide

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and 2- amino[1,3]thiazolo[4,5-d]pyrimidine- 5,7(4H,6H)-dione HRMS calculated for C₁₆H₁₁Cl₂N₇O₃STheo: 449.9943 Found: 449.9927 Rt: 2.36 min MP: 279.9° C. Example 14Methyl 6-[({1-[(3,4- dichlorophenyl) methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl)amino]-3- pyridinecarboxylate

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and methyl 6-amino-3-pyridinecarboxylate HRMS calculated for C₁₈H₁₅Cl₂N₅O₃ Theo: 420.0630Found: 420.0626 Rt: 3.2 min MP: 179° C. Example 15 Methyl 2-[({1-[(3,4-dichlorophenyl) methyl]-5-methyl-1H- 1,2,3-triazol-4-yl}carbonyl)amino]-4- pyridinecarboxylate

1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) and methyl 2-amino-4-pyridinecarboxylate HRMS calculated for C₁₈H₁₅Cl₂N₅O₃ Theo: 420.0630Found: 420.0633 Rt: 3.18 min MP: 172° C.

Example 162-[({1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylicAcid

A mixture of ethyl2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylate(Example 2) (0.482 g, 1.06 mmol) and a 1N NaOH solution (5.5 mL, 5.5mmol) in ethanol (20 mL) was stirred at 50° C. for 45 min. The reactionwas not complete, a 1N NaOH solution (20 mL, 20 mmol) was added and thereaction mixture was stirred for 1h30 at 50° C. The solvent wasevaporated and the residue was acidified with a 1N HCl solution (25 mL)to pH=1. The precipitate formed was filtered, washed with water andcoevaporated with Ethanol. The solid was recrystallised from methanoland washed with DCM to give the title compound as a white solid (418 mg,92%). HRMS calculated for C₁₆H₁₃Cl₂N₅O₃S (M+H)⁺ 426.0194, found:426.0165, Rt: 2.24 min. MP: 262.6° C.

The following compounds were similarly prepared by a method analogous tothat described for Example 16:

TABLE 8 Compound Structure From Physical data Example 17 2-[({1-[(3,4-Dichlorophenyl) methyl]-5-methyl-1H- 1,2,3-triazol-4-yl}carbonyl)amino]- 1,3-oxazole-5- carboxylic acid

Ethyl 2-[({1-[(3,4- dichlorophenyl) methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl)amino]- 1,3-oxazole-5- carboxylate(Intermediate 8) HRMS calculated for C₁₅H₁₁Cl₂N₅O₄ Theo: 396.0266 Found:396.0289 Rt: 2.07 min MP: 201.8° C.

Example 181-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{4-methyl-5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide

A mixture of2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylicacid (Example 16) (0.15 g, 0.35 mmol), methylamine (96 μL, 2.46 mmol),HATU (0.268 g, 0.70 mmol) and DIPEA (80 μL, 0.46 mmol) in DMF wasstirred at 40° C. overnight. The solvent was evaporated and the residuewas washed with water and extracted with DCM (large volume). The organicphase was dried over sodium sulphate, filtered and concentrated. Theresidue was twice purified by flash chromatography eluting with DCM/MeOH(95/5) to give after crystallisation from ether the title compound as awhite solid (33 mg, 21%). HRMS calculated for C₁₇H₁₆Cl₂N₆O₂S (M+H)⁺439.0511, found: 439.0548, Rt: 2.69 min. MP: 218.5° C.

The following compounds were similarly prepared by a method analogous tothat described for Example 18:

TABLE 9 Compound Structure From Physical data Example 19 1-[(3,4-Dichlorophenyl)methyl]- 5-methyl-N-(4- methyl-5-{[(3- methylbutyl)amino]carbonyl}-1,3-thiazol- 2-yl)-1H-1,2,3- triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 4-methyl-1,3- thiazole-5- carboxylic acid (Example16) and isopentylamine HRMS calculated for C₂₁H₂₄Cl₂N₆O₂S Theo: 495.1137Found: 495.1167 Rt: 3.22 min. MP: 174.3° C. Example 20 1-[(3,4-Dichlorophenyl)methyl]- 5-methyl-N-(4- methyl-5-{[(1- methylethyl)amino]carbonyl}-1,3-thiazol- 2-yl)-1H-1,2,3- triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 4-methyl-1,3- thiazole-5- carboxylic acid (Example16) and isopropylamine HRMS calculated for C₁₉H₂₀Cl₂N₆O₂S Theo: 465.0667Found: 465.0626 Rt: 2.94 min. MP: 204.4° C. Example 21 1-[(3,4-Dichlorophenyl)methyl]- N-{5- [(ethylamino)carbonyl]-4-methyl-1,3-thiazol- 2-yl}-5-methyl-1H- 1,2,3-triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 4-methyl-1,3- thiazole-5- carboxylic acid (Example16) and ethylamine HRMS calculated for C₁₈H₁₈Cl₂N₆O₂S Theo: 453.0667Found: 453.0684 Rt: 2.82 min. MP: 194.1° C. Example 22 1-[(3,4-Dichlorophenyl)methyl]- N-[5-({[2- (dimethylamino)ethyl]amino}carbonyl)-4- methyl-1,3-thiazol-2- yl]-5-methyl-1H-1,2,3-triazole-4- carboxamide hydrochloride

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- -4-methyl-1,3- thiazole-5- carboxylic acid (Example16) and N,N- dimethylethylene diamine HRMS calculated for C₂₀H₂₃Cl₂N₇O₂STheo: 496.1089 Found: 496.1131 Rt: 2.48 min. MP: 121° C. Example 231-[(3,4- Dichlorophenyl)methyl]- 5-methyl-N-(5-{[(3- methylbutyl)amino]carbonyl}-1,3-thiazol- 2-yl)-1H-1,2,3- triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 1,3-thiazole-5- carboxylic acid (Intermediate 6) andisopentylamine HRMS calculated for C₂₀H₂₂Cl₂N₆O₂S Theo: 481.0980 Found:481.1023 Rt: 3.12 min. MP: 259.3° C. Example 24 1-[(3,4-Dichlorophenyl)methyl]- 5-methyl-N-[4- methyl-5-(4-morpholinylcarbonyl)- 1,3-thiazol-2-yl]-1H- 1,2,3-triazole-4-carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl-1H- 1,2,3-triazol-4-yl}carbonyl)amino]- 4-methyl-1,3- thiazole-5- carboxylic acid (Example16) and morpholine HRMS calculated for C₂₀H₂₀Cl₂N₆O₃S Theo: 495.0773Found: 495.0808 Rt: 2.71 min. MP: 202.9° C. Example 25 1-[(3,4-Dichlorophenyl)methyl]- 5-methyl-N-{4- methyl-5-[(4-methyl-1-piperazinyl)carbonyl]- 1,3-thiazol-2-yl}-1H- 1,2,3-triazole-4-carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 4-methyl-1,3- thiazole-5- carboxylic acid (Example16) and 1- methylpiperazine HRMS calculated for C₂₁H₂₃Cl₂N₇O₂S Theo:508.1089 Found: 508.1132 Rt: 2.65 min. MP: 216.9° C. Example 26 1-[(3,4-Dichlorophenyl)methyl]- 5-methyl-N-[4- methyl-5-({[2- (methyloxy)ethyl]amino}carbonyl)-1,3- thiazol-2-yl]-1H-1,2,3- triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl-1H- 1,2,3-triazol-4-yl}carbonyl)amino]- 4-methyl-1,3- thiazole-5- carboxylic acid (Example16) and 2-methoxyethyl amine HRMS calculated for C₁₉H₂₀Cl₂N₆O₃S Theo:483.0773 Found: 483.0758 Rt: 2.75 min. MP: 129° C. Example 27 1-[(3,4-Dichlorophenyl)methyl]- N-(5-{[(2- hydroxyethyl)amino]carbonyl}-4-methyl- 1,3-thiazol-2-yl)-5- methyl-1H-1,2,3- triazole-4-carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 4-methyl-1,3- thiazole-5- carboxylic acid (Example16) and 2-aminoethanol HRMS calculated for C₁₈H₁₈Cl₂N₆O₃S Theo: 469.0616Found: 469.0599 Rt: 2.54 min. MP: 166° C. Example 28 1-[(3,4-Dichlorophenyl) methyl]-N-{5- [(dimethylamino) carbonyl]-4-methyl-1,3-thiazol-2-yl}-5- methyl-1H-1,2,3- triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 4-methyl-1,3- thiazole-5- carboxylic acid (Example16) and Dimethyl amine hydrochloride HRMS calculated for C₁₈H₁₈Cl₂N₆O₂STheo: 453.0667 Found: 453.0691 Rt: 2.74 min. MP: 144° C. Example 291-[(3,4- Dichlorophenyl)methyl]- 5-methyl-N-{5- [(methylamino)carbonyl]-1,3-thiazol-2-yl}- 1H-1,2,3-triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 1,3-thiazole-5- carboxylic acid (Intermediate 6) andmethyl amine HRMS calculated for C₁₆H₁₄Cl₂N₆O₂S Theo: 425.0354 Found:425.0347 Rt: 2.62 min. MP: 335.6° C. Example 30 1-[(3,4- Dichlorophenyl)methyl]-N-{5- [(dimethylamino) carbonyl]-1,3-thiazol- 2-yl}-5-methyl-1H-1,2,3-triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 1,3-thiazole-5- carboxylic acid (Intermediate 6) anddimethyl amine HRMS calculated for C₁₇H₁₆Cl₂N₆O₂S Theo: 439.0511 Found:439.0527 Rt: 2.71 min. MP: 304.9° C. Example 31 1-[(3,4-Dichlorophenyl)methyl]- N-(5-{[(2- hydroxyethyl)amino]carbonyl}-1,3-thiazol- 2-yl)-5-methyl-1H- 1,2,3-triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl)amino]- 1,3-thiazole-5- carboxylic acid (Intermediate 6) and2- aminoethanol HRMS calculated for C₁₇H₁₆Cl₂N₆O₃S Theo: 455.0460 Found:455.0503 Rt: 2.51 min. MP: 260.4° C. Example 32 2-[({1-[(3,4-Dichlorophenyl)methyl]- 5-methyl-1H-1,2,3- triazol-4-yl}carbonyl)amino]-N- methyl-4- pyridinecarboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-5-methyl- 1H-1,2,3-triazol-4-yl}carbonyl) amino]-4- pyridinecarboxylic acid (Intermediate 7) andmethyl amine HRMS calculated for C₁₈H₁₆Cl₂N₆O₂ Theo: 419.0790 Found:419.0770 Rt: 2.70 min. MP: 234.1° C.

The following compounds were similarly prepared by a method analogous tothat described for Example 18:

TABLE 10 Compound Structure From Physical data Example 33 1-[(3,4-Dichlorophenyl) methyl]-N-{5- [(ethylamino) carbonyl]-4-methyl-1,3-thiazol-2-yl}-1H- 1,2,3-triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-1H-1,2,3- triazol-4-yl}carbonyl)amino]-4- methyl-1,3-thiazole- 5-carboxylic acid(Intermediate 15) and ethyl amine HRMS calculated for C₁₇H₁₆Cl₂N₆O₂STheo: 439.0511 Found: 439.0522 Rt: 2.67 min. MP: 210.6° C. Example 341-[(3,4- Dichlorophenyl) methyl]-N-{4- methyl-5- [(methylamino)carbonyl]-1,3- thiazol-2-yl}-1H- 1,2,3-triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-1H-1,2,3- triazol-4-yl}carbonyl)amino]-4- methyl-1,3-thiazole- 5-carboxylic acid(Intermediate 15) and methyl amine HRMS calculated for C₁₆H₁₄Cl₂N₆O₂STheo: 425.0354 Found: 425.0362 Rt: 2.54 min. MP: 210.4° C.

Example 351-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide

A mixture of2-[({1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylicacid (Intermediate 14) (0.18 g, 0.45 mmol), 2-aminoethanol (32 μL, 1.2eq), HATU (0.22 g, 1.3 eq) and DIPEA (100 μL, 1.3 eq) in DMF (20 mL) wasstirred at 40° C. for 48 hours. The solvent was evaporated and theresidue was washed with water and extracted with DCM. The insolublecompound was filtered and washed with a mixture of acetonitrile/methanol80/20 and then purified by flash chromatography eluting with DCM/MeOH(95/5) to give the title compound as a white solid (60 mg, 30%). HRMScalculated for C₁₆H₁₄Cl₂N₆O₃S (M+H)⁺ 441.0303, found: 441.0339, Rt: 2.39min. MP: 274.8° C.

Example 36N-[5-(Aminocarbonyl)-1,3-thiazol-2-yl]-1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide

To a suspension of2-[({1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylicacid (Intermediate 14) (0.14 g, 3.5 mmol) in THF (10 mL), was added 1drop of DMF and oxalyl chloride (0.06 mL, 2 eq). The reaction wasstirred to room temperature for 3 hours. The reaction was evaporated invacuo. After dissolution in THF (10 mL), the residue was treated withammonia (gas) for 5 min. The reaction was stirred at room temperaturefor 1 hour. After filtration, the filtrate was concentrated and purifiedthrough a bed of silica eluting with DCM/MeOH, 98/2. Afterrecrystallisation from methanol, the title compound was obtained as awhite solid (10 mg, 7%). HRMS calculated for C₁₄H₁₀Cl₂N₆O₂S (M+H)⁺397.0041, found: 397.0044, Rt: 2.40 min. MP: 280.9° C.

The following compounds were similarly prepared by a method analogous tothat described for Example 36:

TABLE 11 Compound Structure From Physical data Example 37 N-[5-(Aminocarbonyl)-4- methyl-1,3-thiazol-2- yl]-1-[(3,4- dichlorophenyl)methyl]-1H-1,2,3- triazole-4- carboxamide

2-[({1-[(3,4- Dichlorophenyl) methyl]-1H-1,2,3- triazol-4-yl}carbonyl)amino]- 4-methyl-1,3- thiazole-5-carboxylic acid(Intermediate 15) HRMS calculated for C₁₅H₁₂Cl₂N₆O₂S Theo: 411.0198Found: 411.0186 Rt: 2.47 min. MP: 283° C.

Example 381-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-1,3,4-thiadiazol-2-yl-1H-1,2,3-triazole-4-carboxamide

A mixture of ethyl5-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3,4-thiadiazole-2-carboxylate(Example 3) (0.302 g, 0.68 mmol) and a 1N NaOH solution (7 mL, 7 mmol)in ethanol (20 mL) was stirred at 50° C. for 1 hour. The solvent wasevaporated and the residue was acidified with a 1N HCl solution. Theprecipitate formed was filtered and the solid was recrystallised fromacetonitrile to give the title compound as a white solid (124 mg, 49%).HRMS calculated for C₁₃H₁₀Cl₂N₆OS (M+H)⁺ 369.0092, found: 369.0107, Rt:2.64 min. MP: 215.6° C.

Example 391-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide

To a suspension of1-[(3,4-dichlorophenyl)methyl]-N-(5-formyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide(Example 5) (1.2 g, 30 mmol), in a mixture of DCM/MeOH, was added sodiumborohydride (130 mg). The reaction was stirred at room temperature for 1hour. After evaporation, the residue was poured in a mixture ofwater/concentrated HCl solution and extracted with ethyl acetate. Asolid was formed and filtered. The filtrate was dried over sodiumsulphate and evaporated in vacuo. The combined solids wererecrystallised from acetonitrile to give the title compound as a yellowsolid (0.8 g, 67%). HRMS calculated for C₁₅H₁₃Cl₂N₅O₂S (M+H)⁺ 398.0245,found: 398.0205, Rt: 2.59 min. MP: 170.5° C.

The following compounds were similarly prepared by a method analogous tothat described for Example 39:

TABLE 12 Compound Structure From Physical data Example 40 1-[(3,4-Dichlorophenyl)methyl]- N-[5-(hydroxymethyl)- 1,3-thiazol-2-yl]-5-[(methyloxy)methyl]- 1H-1,2,3-triazole-4- carboxamide

1-[(3,4- dichlorophenyl) methyl]-N-(5- formyl-1,3-thiazol- 2-yl)-5-[(methyloxy) methyl]-1H-1,2,3- triazole-4- carboxamide (Intermediate 9)HRMS calculated for C₁₆H₁₅Cl₂N₅O₃S Theo: 428.0351 Found: 428.0341 Rt:2.65 min. MP: 205° C.

Example 411-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-4-methyl-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide

To a solution of ethyl2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylate(Example 2) (0.1 g, 0.22 mmol) in THF was added a 1M solution of DIBAL-Hin toluene (2.76 mL, 6 eq) and the reaction was stirred to roomtemperature for 27 hours. Ether was added followed by solid NH₄Cl. After30 min, water was added and the mixture was filtered. The aqueous phasewas extracted with ether, dried over sodium sulphate and evaporated.After purification by flash chromatography, eluting with DCM/MeOH 95/5,and crystallisation from acetonitrile, the title compound was obtainedas a white solid (3 mg, 3%). HRMS calculated for C₁₆H₁₅Cl₂N₅O₂S (M+H)⁺412.0402, found: 412.0409, Rt: 2.65 min. MP: 161.8° C.

The following compounds were similarly prepared by a method analogous tothat described for Example 41:

TABLE 13 Compound Structure From Physical data Example 42 1-[(3,4-Dichlorophenyl) methyl]-N-[5- (hydroxymethyl)- 1,3,4-thiadiazol-2-yl]-5-methyl-1H-1,2,3- triazole-4- carboxamide

Ethyl 5-[({1-[(3,4- dichlorophenyl) methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl)amino]- 1,3,4-thiadiazole- 2-carboxylate(Example 3) HRMS calculated for C₁₄H₁₂Cl₂N₆O₂S Theo: 399.0198 Found:399.0216 Rt: 2.50 min. MP: 153.6° C. Example 43 1-[(3,4- Dichlorophenyl)methyl]-N-[4-(2- hydroxyethyl)-1,3- thiazol-2-yl]-5- methyl-1H-1,2,3-triazole-4- carboxamide

Methyl {2-[({1- [(3,4- dichlorophenyl) methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl)amino]- 1,3-thiazol-4- yl}acetate(Example 8) HRMS calculated for C₁₆H₁₅Cl₂N₅O₂S Theo: 412.0402 Found:412.0374 Rt: 2.69 min. LC/MS: m/z 412 (M + H)⁺ Rt: 3.0 min Example 441-[(3,4- Dichlorophenyl) methyl]-N-[4- (hydroxymethyl)-2-pyridinyl]-5-methyl- 1H-1,2,3-triazole-4- carboxamide

Methyl 2-[({1-[(3,4- dichlorophenyl) methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl) amino]-4-pyridine carboxylate (Example15) HRMS calculated for C₁₇H₁₅Cl₂N₅O₂ Theo: 392.0681 Found: 392.0716 Rt:2.65 min. MP: 191° C.

Example 45N-{1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}-6-(methyloxy)-1,3-benzothiazole-2-carboxamide

A mixture of1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-amine(Intermediate 19) (0.1 g, 0.39 mmol),6-(methyloxy)-1,3-benzothiazole-2-carboxamide (81 mg, 1 eq), HATU (0.192g, 1.3 eq) and DIPEA (0.12 mL, 1.3 eq) in DMF (5 mL) was stirred at 45°C. for 48 hours. The solvent was evaporated and the residue was washedwith water and extracted with DCM. The organic phase was dried oversodium sulphate, filtered and concentrated. The residue was purified byflash chromatography eluting with DCM/MeOH (99/1) to give afterrecrystallisation from acetonitrile the title compound as pink palecrystals (110 mg, 65%). HRMS calculated for C₁₉H₁₅Cl₂N₅O₂S (M+H)⁺448.0402, found: 448.0406, Rt: 3.08 min. MP: 176° C.

Example 46{2-[({1-[(3,4-Dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}methypamino]-1,3-thiazol-5-yl}methanol

To a solution of4-(bromomethyl)-1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole(Intermediate 17) (0.21 g, 0.65 mmol) in acetonitrile was added(2-amino-1,3-thiazol-5-yl)methanol (0.175 g, 2 eq) followed by potassiumcarbonate (0.185 g, 2 eq) The reaction was stirred at 40° C. for 2 days.After evaporation, the residue was dissolved in ether and ethyl acetateand washed with water. The organic phase was dried over sodium sulphate,filtered and evaporated. The compound was purified by flashchromatography eluting with DCM/MeOH (92/8). The title compound wasobtained as an ochre powder (3 mg, 1.25%). HRMS calculated forC₁₄H₁₃Cl₂N₅OS (M+H)⁺ 370.0296, found: 370.0297, Rt: 2.35 min. LC/MS: m/z370 (M+H)+ Rt: 2.60 min.

BIOLOGICAL ASSAY

The compounds of the present invention may be analysed in vitro for SCDactivity using an assay based on the production of [³H]H₂O, which isreleased during the enzyme-catalyzed generation of the monounsaturatedfatty acyl CoA product. The assay is performed in a 96-well filtrationplates. The titrated substrate used in the assay is the [9,10-³H]stearoyl Coenzyme A. After incubation for 6 minutes of SCD-containingrat microsomes (2 μg protein) and substrate (1 μM), the labelled fattyacid acyl-CoA species and microsomes are absorbed with charcoal andseparated from [³H]H₂O by centrifugation. The formation of [³H]H₂O isused as a measure of SCD activity. Compounds at concentrations startingat 10 μM to 0.1 nM or vehicle (DMSO) are preincubated for 5 minutes withthe microsomes before addition of the substrate. Theconcentration-responses are fitted with sigmoidal curves to obtain 10₅₀values.

All of the synthetic Example compounds 1-46 tested by the abovedescribed in vitro assay for SCD activity were found to exhibit anaverage pIC₅₀ value of greater than 5.5.

The following compounds were also prepared and when tested by the abovedescribed in vitro assay for SCD activity were found to exhibit anaverage pIC₅₀ value of less than 5.

Name Structure 1-[(4-fluorophenyl)methyl]-5- methyl-N-(5-methyl-3-isoxazolyl)-1H-1,2,3-triazole- 4-carboxamide

Methyl 2-[({1-[(3,4- dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl)amino]-1-methyl-1H-imidazole-5-carboxylate

1-[(3,4- Dichlorophenyl)methyl]-N-(5- formyl-4-methyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3- triazole-4-carboxamide

Methyl 2-[({1-[(3,4- dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl)amino]-5-ethyl-1,3-thiazole-4-carboxylate

1-[(3,4- Dichlorophenyl)methyl]-5- methyl-N-[5-(methyloxy)-1,3-benzothiazol-2-yl-1H-1,2,3- triazole-4-carboxamide

1-[(3,4- Dichlorophenyl)methyl]-N-[5- (1-hydroxy-1-methylethyl)-1,3,4-thiadiazol-2-yl]-5- methyl-1H-1,2,3-triazole-4- carboxamide

Methyl 6-[({1-[(3,4- Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl)amino]-2- pyridinecarboxylate

The following compounds were also prepared and when tested by the abovedescribed in vitro assay for SCD activity were found to exhibit anaverage pIC₅₀ value of between 5 and 5.5.

Name Structure 2-[({1-[(3,4- Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4- yl}carbonyl)amino]-1-methyl-1H-imidazole-5-carboxylic acid

2-[({1-[(3,4- Dichlorophenyl)methyl]-5- methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1-methyl- 1H-imidazole-5-carboxylic acid

1. A method for treating and/or preventing diseases or conditions causedby or associated with an abnormal plasma lipid profile with an effectiveamount of a compound of formula (I) or pharmaceutically acceptable saltthereof

wherein: X represents —CONH—, —NHCO— or —CH₂NH—; R¹ represents:—C₆₋₁₀aryl optionally substituted by one, two or three groupsindependently selected from: —C₁₋₃alkyl, —C₁₋₆alkoxy, —C₁₋₆haloalkyl,—OC₁₋₆haloalkyl, —OC₃₋₆cycloalkyl or halogen; R² represents hydrogen,—C₁₋₆alkyl or —C₁₋₃alkylOC₁₋₃alkyl; R³ represents: —C₅₋₉heteroaryloptionally substituted by one, two or three groups independentlyselected from: —C₁₋₃alkyl, —C₁₋₆alkoxy, —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH, —C═O, —CHO,—C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl,—OC₁₋₆haloalkyl, —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl, or halogen; R⁴represents —H or —C₁₋₃alkyl; R⁵ represents —H or —C₁₋₃alkyl; R⁶represents —H or —C₁₋₆alkyl; R⁷ represents —H or —C₁₋₃alkyl; R⁸represents —H or —C₁₋₃alkyl; and R⁹ represents —C₆heterocycle which isoptionally substituted by a group independently selected from:—C₁₋₆alkyl; or a pharmaceutically acceptable salt thereof, with theproviso that the compound of formula (I) is notN-1,3-benzodioxol-5-yl-1-[(4-flurophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide

orN-(6-acetyl-1,3-benzodioxol-5-yl)-1-[(4-methylphenyl)methyl]-1H-1,2,3-triazole-4-carboxamide

and further provided that R3 is not an optionally substitutedtetrahydronapthyridine when X is —NHCO or —CONH in a human in needthereof with an effective amount of a compound of Formula (I) whereinsaid disease or condition is selected from the group dyslipidemia,hypoalphalipoproteinemia, hyperbetalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, angina, ischemia, cardiac ischemia, stroke,myocardial infarction, atherosclerosis, obesity, Type I diabetes, TypeII diabetes, insulin resistance, hyperinsulinaemia and metabolicsyndrome; peripheral vascular disease, reperfusion injury, angioplasticrestenosis, hypertension, vascular complications of diabetes,thrombosis, hepatic steatosis, non-alcoholic steatohepatitis (NASH) andother diseases related to accumulation of lipids in the liver; eczema,acne, psoriasis, skin ageing, keloid scar formation or prevention, anddiseases related to production or secretions from mucous membranes;cancer, neoplasia, malignancy, metastases, tumours (benign ormalignant), carcinogenesis, hepatomas and the like; mild cognitiveimpairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy(CAA) or dementia associated with Down Syndrome (DS) and otherneurodegenerative diseases characterized by the formation oraccumulation of amyloid plaques comprising Aβ42.
 2. The method accordingto claim 1 wherein the disease or condition is selected from acne,psoriasis, skin ageing, dyslipidemia, hypertriglyceridemia,atherosclerosis, obesity, Type II diabetes, insulin resistance,hyperinsulinaemia, hepatic steatosis and non-alcoholic steatohepatitis(NASH).
 3. The method according to claim 1 wherein the disease orcondition is for treatment or prevention of acne.
 4. The methodaccording to claim 1 wherein X represents —CONH—.
 5. The methodaccording to claim 1 wherein X represents —NHCO—.
 6. The methodaccording to claim 1 wherein X represents —CH₂NH—.
 7. The methodaccording to claim 1 wherein R¹ represents phenyl substituted by twogroups independently selected from halogen.
 8. The method according toclaim 1 wherein R² represents hydrogen or —C₁₋₃alkyl.
 9. The methodaccording to claim 1 wherein R³ represents —C₅heteroaryl containing 5ring-atoms 1, 2, 3 or 4 of which are hetero-atoms independently selectedfrom nitrogen, oxygen or sulphur and the remaining ring-atoms arecarbon, optionally substituted by one, two or three groups independentlyselected from: —C₁₋₃alkyl, —C₁₋₆alkoxy, —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH, —C(═O), —CHO,—C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl,—OC₁₋₆haloalkyl, —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl or halogen.
 10. Themethod according to claim 1 wherein R³ represents —C₉heteroarylcontaining 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atomsindependently selected from nitrogen or sulphur and the remainingring-atoms are carbon, optionally substituted by one, two or threegroups independently selected from: —C₁₋₃alkyl, —C₁₋₆alkoxy, —CO₂R⁴,—C(═O)NR⁵R⁶, —C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH, —C(═O), —CHO,—C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl,—OC₁₋₆haloalkyl, —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl or halogen.
 11. Themethod according to claim 1 wherein R³ represents —C₆heteroaryloptionally substituted by one, two or three groups independentlyselected from: —C₁₋₃alkyl, —C₁₋₆alkoxy, —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylO—C₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH, —C(═O), —CHO,—C₁₋₃alkylCO_(2—)C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl,—OC₁₋₆haloalkyl, —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl or halogen.
 12. Themethod according to claim 1 wherein the C₅₋₉heteroaryl is a monocyclicor bicyclic ring system including an aromatic cyclic group containing 5to 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atoms independentlyselected from nitrogen, oxygen and sulphur and the remaining ring-atomsare carbon.
 13. The method according to claim 12 wherein the bicyclicstructure contains at least one ring which is aromatic.
 14. The methodaccording to claim 1 wherein the C₅₋₉heteroaryl is an isoxazole,oxazole, thiazolopyrimidine, imidazole, thiazole, benzothiazole,thiadiazole, oxadiazole or pyridine.
 15. The method according to claim 1wherein the C₅₋₉heteroaryl is a thiazole, benzothiazole, thiadiazole,oxazole, pyridine or thiazolopyrimidine.
 16. The method according toclaim 1 wherein the compound is selected from:1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[6-(methyloxy)-1,3-benzothiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide,Ethyl2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylate,Ethyl5-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3,4-thiadiazole-2-carboxylate,Methyl2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylate,1-[(3,4-Dichlorophenyl)methyl]-N-(5-formyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{5-[(methyloxy)methyl]-1,3,4-thiadiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,Methyl{2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazol-4-yl}acetate,Ethyl2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate,1-[(3,4-Dichlorophenyl)methyl]-N-(4,5-dimethyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,Ethyl2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-benzothiazole-6-carboxylate,Ethyl{2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-5-methyl-1,3-thiazol-4-yl}acetate,1-[(3,4-Dichlorophenyl)methyl]-N-(5,7-dioxo-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-d]pyrimidin-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,Methyl6-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-3-pyridinecarboxylate,Methyl2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-pyridinecarboxylate,2-[({1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylicacid,2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-oxazole-5-carboxylicacid,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{4-methyl-5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(4-methyl-5-{[(3-methylbutyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(4-methyl-5-{[(1-methylethypamino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(ethylamino)carbonyl]-4-methyl-1,3-thiazo1-2-yl}-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-[5-({[2-(dimethylamino)ethyl]amino}carbonyl)-4-methyl-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-(5-{[(3-methylbutyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[4-methyl-5-(4-morpholinylcarbonyl)-1,3-thiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{4-methyl-5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-[4-methyl-5-({[2-(methyloxy)ethyl]amino}carbonyl)-1,3-thiazol-2-yl]-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-4-methyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(dimethylamino)carbonyl]-4-methyl-1,3-thiazol-2-yl}-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-{5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(dimethylamino)carbonyl]-1,3-thiazol-2-yl}-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide,2-[({1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-N-methyl-4-pyridinecarboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-{5-[(ethylamino)carbonyl]-4-methyl-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-{4-methyl-5-[(methylamino)carbonyl]-1,3-thiazol-2-yl}-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-(5-{[(2-hydroxyethyl)amino]carbonyl}-1,3-thiazol-2-yl)-1H-1,2,3-triazole-4-carboxamide,N-[5-(Aminocarbonyl)-1,3-thiazol-2-yl]-1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide,N-[5-(Aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-5-methyl-N-1,3,4-thiadiazol-2-yl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-5-[(methyloxy)methyl]-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-4-methyl-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-[5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,1-[(3,4-Dichlorophenyl)methyl]-N-[4-(hydroxymethyl)-2-pyridinyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide,N-{1-[(3,4-Dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}-6-(methyloxy)-1,3-benzothiazole-2-carboxamide,or{2-[({1-[(3,4-Dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}methypamino]-1,3-thiazol-5-yl}methanol,or a pharmaceutically acceptable salt thereof.
 17. A method of treatingand/or preventing a disease or a condition susceptible to ameliorationby an SCD inhibitor in a human in need thereof with an effective amountof a compound of formula (I) or pharmaceutically acceptable salt thereof

wherein: X represents —CONH—, —NHCO— or —CH₂NH—; R¹ represents:—C₆₋₁₀aryl optionally substituted by one, two or three groupsindependently selected from: —C₁₋₃alkyl, —C₁₋₆alkoxy, —C₁₋₆haloalkyl,—OC₁₋₆haloalkyl, —OC₃₋₆cycloalkyl or halogen; R² represents hydrogen,—C₁₋₆alkyl or —C₁₋₃alkylOC₁₋₃alkyl; R³ represents: —C₅₋₉heteroaryloptionally substituted by one, two or three groups independentlyselected from: —C₁₋₃alkyl, —C₁₋₆alkoxy, —CO₂R⁴, —C(═O)NR⁵R⁶,—C(═O)NHC₁₋₃alkylNR⁷R⁸, —C(═O)NHC₁₋₃alkylOC₁₋₃alkyl,—C(═O)NHC₁₋₃alkylOH, —C(═O)R⁹, —C₁₋₆alkylOH, —C═O, —CHO,—C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl, —C₁₋₆haloalkyl,—OC₁₋₆haloalkyl, —OC₃₋₆cycloalkyl, —C₃₋₆cycloalkyl, or halogen; R⁴represents —H or —C₁₋₃alkyl; R⁵ represents —H or —C₁₋₃alkyl; R⁶represents —H or —C₁₋₆alkyl; R⁷ represents —H or —C₁₋₃alkyl; R⁸represents —H or —C₁₋₃alkyl; and R⁹ represents —C₆heterocycle which isoptionally substituted by a group independently selected from:—C₁₋₆alkyl; or a pharmaceutically acceptable salt thereof, with theproviso that the compound of formula (I) is notN-1,3-benzodioxol-5-yl-1-[(4-flurophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide

orN-(6-acetyl-1,3-benzodioxol-5-yl)-1-[(4-methylphenyl)methyl]-1H-1,2,3-triazole-4-carboxamide

and further provided that R3 is not an optionally substitutedtetrahydronapthyridine when X is —NHCO or —CONH.
 18. A method accordingto claim 17 wherein the disease or conditions susceptible toamelioration by an SCD inhibitior is selected from the group consistingof dyslipidemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, angina, ischemia, cardiac ischemia, stroke,myocardial infarction, atherosclerosis, obesity, Type I diabetes, TypeII diabetes, insulin resistance, hyperinsulinaemia and metabolicsyndrome; peripheral vascular disease, reperfusion injury, angioplasticrestenosis, hypertension, vascular complications of diabetes,thrombosis, hepatic steatosis, non-alcoholic steatohepatitis (NASH) andother diseases related to accumulation of lipids in the liver; eczema,acne, psoriasis, skin ageing, keloid scar formation or prevention, anddiseases related to production or secretions from mucous membranes;cancer, neoplasia, malignancy, metastases, tumours (benign ormalignant), carcinogenesis, hepatomas and the like; mild cognitiveimpairment (MCI), Alzheimer's Disease (AD), cerebral amyloid angiopathy(CAA), dementia associated with Down Syndrome (DS) and any otherneurodegenerative diseases characterized by the formation oraccumulation of amyloid plaques comprising Aβ42.
 19. The methodaccording to claim 18 wherein the disease or condition is selectedfromacne, psoriasis, skin ageing, dyslipidemia, hypertriglyceridemia,atherosclerosis, obesity, Type II diabetes, insulin resistance,hyperinsulinaemia, hepatic steatosis and non-alcoholic steatohepatitis(NASH).
 20. The method according to claim 18 wherein the disease orcondition is for the treatment and/or prevention of acne.